Plants and Cancer Treatment

*Bassam Hassan*

### **Abstract**

In this century, cancer has become one of the major problems and diseases that have caused predominant death, and it will even surpass heart diseases. Since World War I, chemotherapy has become as one of the most important and significant treatments of cancer. Even if it can cure cancer, it is found to cause several critical side effects. Over the past 20 years, many types of new therapies have emerged; some of them were extracted from plants that are found to be effective and safe. Moreover, it has been approved that several plants, herbs, and vegetables can prevent or reduce incidence of cancer in several sites of the human body. Besides, researchers found that they are a great source for developing and producing new, effective, tolerable, and safe anticancer drugs compared with the synthetic ones. As a result of that, researchers recommended future studies to focus more on plant as a source for safe and effective anticancer treatment.

**Keywords:** cancer, plants, anti-growth, apoptosis, treatment

### **1. Cancer background**

During this century, cancer has become one of the major problems and diseases which has caused predominant death, and it will even surpass heart diseases. Many of the researchers begin to use the term lifetime risk for cancer patients which refer to the time that cancer will progress and developed or the time that the patient will die because of cancer. Cancer does not represent only one disease but it is a group involving about 100 diseases. It is characterized by two things: Firstly there is no control for the growth of cancer cells, and secondly it is the ability of the cancer cells to metastasize and migrate from the original site to different parts of the body. There are two types of tumors which are malignant and benign. Cancer can attack any person, and its occurrence increases as the age of the individual increases too [1, 2]. There are many problems (i.e., side effects) associated with cancer diseases either solid or hematological cancer such as nausea, vomiting, diarrhea, constipation, hypercalcemia, pain, loss of appetite, anemia, fatigue, cachexia, leucopenia, neutropenia, and thrombocytopenia. However the major problems are nausea and vomiting, neutropenia, anemia, thrombocytopenia, and hypercalcemia. Hence due to these reasons, cancer is considered as one of the major diseases that will affect the quality of life [3–6].

### **2. Chemotherapy background**

Chemotherapy was developed and used since the Word War I from the chemical weapon program of the United States of America (USA). Since then chemotherapy

has become as one of the most important and significant treatments of cancer. Its main mechanism of action is by killing the cancer cells which are characterized by their high multiplication and growth rate. It will also kill all the cancer cells that had broken off from the main tumor and spread to the blood or lymphatic system or any part of the body. This killing process of cells is either by a direct effect on deoxyribonucleic acid (DNA) or an effect on the factors involved in mitosis by inhibition of its synthesis or production or uses [7–9]. Chemotherapy drug may lead to complete cure for some types of cancers or may suppress the growth of others or may prevent their spread to other parts of the body. So many types of new therapies have emerged over the past 20 years. Some of them were straight forward, effective, and safe and some have many side effects. However when comparing chemotherapy with other types of treatments, it still remains potentially high risk with many side effects which are difficult to manage. The chemotherapy used required the involvement of various clinical professionals during its various stages of administration, and enormous patient health care is needed to overcome its side effects [7, 10].

## **3. Chemotherapy side effects**

The goal of chemotherapy is to be as effective as possible with tolerable side effects, since the dose of chemotherapy will be toxic to the cancer cells as well as to the normal cells. A proportion of the cancer patients suffer from only mild side effects, whereas others may suffer from serious side effects [10–12].

These side effects are classified as:


Occurrence of specific side effects will vary according to the chemotherapy used. The most common side effects experienced are nausea and vomiting, anemia, hair lost, bleeding, thrombocytopenia, hyperuricemia, bone marrow depression, alopecia, and mucositis. So different parameters must be taken into consideration to prevent, reduce, and overcome these side effects [10–12].

**143**

*Plants and Cancer Treatment*

**4. Plants and cancer**

hence ulceration" [14].

chemotypes [14–16, 19].

*DOI: http://dx.doi.org/10.5772/intechopen.90568*

compounds, i.e., anticancer compounds [13–15].

**5. Plants and cancer treatment and prevention**

Herbal medicine has been used as a major treatment for cancer in various countries in the Middle East and Europe long time ago. Recent reports released by the World Health Organization (WHO) showed that although many advanced countries have considered traditional herbal treatment as an official treatment for cancer, only 5–15% of these herbs have been investigated to detect their bioactive

According to the two famous Islamic physicians (Rhazes and Avicenna), diseases need to be treated by using a scheme which consists of three options; the first option will be by using physiotherapy and diet, the second one will be by using drugs, and the last option will be surgery. Drugs used on that time have been classified as simple and compound drugs. Treatment of any disease will start with the simple one to avoid drug–drug interaction; unless it did not work, then physician will use the compound drugs, and when second option failed too, then surgery will be used [15]. Regarding cancer treatment, the Islamic scholar "Avicenna" mentioned that "if it is the start of a cancer, it is possible to make it static and prevent it from growth and

Researchers mentioned that herbal-based medicines are found to be one of the best choices for treating and/or preventing incidence of cancer. This is mainly because of the varieties of active substances that plants contained which work against many types of cancers in several mechanisms. These compounds can be extracted and can be used alone or in combination with other anticancer treatments. In comparison with synthetic drugs, these natural compounds are found to be naturally available, cheaper, and easy to administered orally and have low or minimal side effects, and they are found to be rich of various biologically active

"Chemopreventive agents against many types of cancers like; *Abrus precatorius* on Yoshida sarcoma, *Albizia lebbeck* on sarcoma, and *Alstonia scholaries* on forestomach carcinoma". Other plants characterized by anticancer activity like "*Anacardium occidentale* in hepatoma, *Asparagus racemosus* in human epidermoid carcinoma, *Boswellia serrata* in human epidermal carcinoma of the nasopharynx, *Erythrina suberosa* in sarcoma, *Euphorbia hirta* in Freund virus leukemia, *Gynandropsis pentaphylla* in hepatoma, *Nigella sativa* in Lewis lung carcinoma, *paederia foetida* in human epidermoid carcinoma of the nasopharynx, *picrorhiza kurroa* in hepatic

One of the most critical problems associated with cancer treatment is chemotherapy resistance, that's why researchers trying their best to prevent or reduce incidence of resistance by detecting new anticancer agents as an alternate [14].

have not only the ability to work as anticancer agents but also to restore chemotherapy sensitivity, for example, tetrandrine which is an active alkaloid compound extracted from plant enhances doxorubicin anticancer activity against resistant MCF-1/DOX cells in vivo via modulating P-gp-mediated drug efflux. Another natural compound is quercetin (flavonoid) which restores daunorubicin chemosensitivity in resistant HL-60/DOX and K562/DOX cell lines via suppression of P-gp

Thazin and colleagues mentioned that natural compounds extracted from plants

Avni and colleagues mentioned there are several plants work as

cancers, and *Withania somnifera* in various tumors" [20].

### **4. Plants and cancer**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

has become as one of the most important and significant treatments of cancer. Its main mechanism of action is by killing the cancer cells which are characterized by their high multiplication and growth rate. It will also kill all the cancer cells that had broken off from the main tumor and spread to the blood or lymphatic system or any part of the body. This killing process of cells is either by a direct effect on deoxyribonucleic acid (DNA) or an effect on the factors involved in mitosis by inhibition of its synthesis or production or uses [7–9]. Chemotherapy drug may lead to complete cure for some types of cancers or may suppress the growth of others or may prevent their spread to other parts of the body. So many types of new therapies have emerged over the past 20 years. Some of them were straight forward, effective, and safe and some have many side effects. However when comparing chemotherapy with other types of treatments, it still remains potentially high risk with many side effects which are difficult to manage. The chemotherapy used required the involvement of various clinical professionals during its various stages of administration, and enormous patient health care is needed to overcome its side

The goal of chemotherapy is to be as effective as possible with tolerable side effects, since the dose of chemotherapy will be toxic to the cancer cells as well as to the normal cells. A proportion of the cancer patients suffer from only mild side

1.Acute, which develop within 24 hours after chemotherapy administration

2.Delayed, which developed after 24 hours and up to 6–8 weeks after chemo-

4.Late/long term, which developed after months or years of chemotherapy

Occurrence of specific side effects will vary according to the chemotherapy used. The most common side effects experienced are nausea and vomiting, anemia, hair lost, bleeding, thrombocytopenia, hyperuricemia, bone marrow depression, alopecia, and mucositis. So different parameters must be taken into consideration to

effects, whereas others may suffer from serious side effects [10–12].

3.Short term, combination of both acute and delayed effect

5.Expected, which developed among 75% of the patients

7.Uncommon, happened less than 15% of the patients

9.Very rare, occur on less than 1% of the patients [10–12]

prevent, reduce, and overcome these side effects [10–12].

6.Common, occurred in 25–75% of the patients

8.Rare, occur in only 5% of the patients

**142**

effects [7, 10].

**3. Chemotherapy side effects**

therapy treatments

treatment

These side effects are classified as:

Herbal medicine has been used as a major treatment for cancer in various countries in the Middle East and Europe long time ago. Recent reports released by the World Health Organization (WHO) showed that although many advanced countries have considered traditional herbal treatment as an official treatment for cancer, only 5–15% of these herbs have been investigated to detect their bioactive compounds, i.e., anticancer compounds [13–15].

### **5. Plants and cancer treatment and prevention**

According to the two famous Islamic physicians (Rhazes and Avicenna), diseases need to be treated by using a scheme which consists of three options; the first option will be by using physiotherapy and diet, the second one will be by using drugs, and the last option will be surgery. Drugs used on that time have been classified as simple and compound drugs. Treatment of any disease will start with the simple one to avoid drug–drug interaction; unless it did not work, then physician will use the compound drugs, and when second option failed too, then surgery will be used [15].

Regarding cancer treatment, the Islamic scholar "Avicenna" mentioned that "if it is the start of a cancer, it is possible to make it static and prevent it from growth and hence ulceration" [14].

Researchers mentioned that herbal-based medicines are found to be one of the best choices for treating and/or preventing incidence of cancer. This is mainly because of the varieties of active substances that plants contained which work against many types of cancers in several mechanisms. These compounds can be extracted and can be used alone or in combination with other anticancer treatments. In comparison with synthetic drugs, these natural compounds are found to be naturally available, cheaper, and easy to administered orally and have low or minimal side effects, and they are found to be rich of various biologically active chemotypes [14–16, 19].

Avni and colleagues mentioned there are several plants work as "Chemopreventive agents against many types of cancers like; *Abrus precatorius* on Yoshida sarcoma, *Albizia lebbeck* on sarcoma, and *Alstonia scholaries* on forestomach carcinoma". Other plants characterized by anticancer activity like "*Anacardium occidentale* in hepatoma, *Asparagus racemosus* in human epidermoid carcinoma, *Boswellia serrata* in human epidermal carcinoma of the nasopharynx, *Erythrina suberosa* in sarcoma, *Euphorbia hirta* in Freund virus leukemia, *Gynandropsis pentaphylla* in hepatoma, *Nigella sativa* in Lewis lung carcinoma, *paederia foetida* in human epidermoid carcinoma of the nasopharynx, *picrorhiza kurroa* in hepatic cancers, and *Withania somnifera* in various tumors" [20].

One of the most critical problems associated with cancer treatment is chemotherapy resistance, that's why researchers trying their best to prevent or reduce incidence of resistance by detecting new anticancer agents as an alternate [14].

Thazin and colleagues mentioned that natural compounds extracted from plants have not only the ability to work as anticancer agents but also to restore chemotherapy sensitivity, for example, tetrandrine which is an active alkaloid compound extracted from plant enhances doxorubicin anticancer activity against resistant MCF-1/DOX cells in vivo via modulating P-gp-mediated drug efflux. Another natural compound is quercetin (flavonoid) which restores daunorubicin chemosensitivity in resistant HL-60/DOX and K562/DOX cell lines via suppression of P-gp

expression. Curcumin also increases vincristine chemotherapy activity in SGC7901/ VCR cell lines by suppressing ABC transporters such as P-gp, MRP1, and ABCG2 proteins [21].

Jana and colleagues conducted in vitro study to determine the anticancer, antiproliferative, and cytotoxic effect of brassinosteroids (BRs) which are steroids extracted from plants against (MCF-7/MDA-MB-468) breast and (LNCaP/ DU-145) prostate cancer cell lines and normal cell line. Results showed that RBs significantly arrested MCF-7, MDA-MB-468, and LNCaP cells in G1 phase of the cell cycle and induced apoptosis in MDA-MB-468, LNCaP, and slightly in the DU-145 cells, without any toxic effect against normal cell lines. These results support the point that RB compounds are a promising source for anticancer drugs [22]. Another in vitro study is conducted to detect the antiproliferative and cytotoxic effect of the aqueous extract of *A. ascalonicum* against Wehi164 (mouse fibrosarcoma cells), Jurkat (human acute T-cell leukemia) and K562 (human erythroleukemia), and human umbilical vein endothelial cells (HUVEC) as a normal cell line. Results showed that the extract showed a significant antiproliferative effect against all cancer cell lines and a dose and time cytotoxic effect against them with a very low cytotoxic effect against a normal cell line. These results showed that the *Allium ascalonicum* plant is a promising source for a potent anticancer treatment for several types of cancers [23].

About cancer prevention, it has been approved that several plants, herbs, and vegetables can prevent or reduce the incidence of cancer in several sites of the human body [14].

An in vitro study is conducted by a group of researchers trying to detect the ability of ethyl acetate extract of onion (EEO) to cause inhibition for cancer growth and cause apoptosis in human breast cancer MDA-MB-231. Results showed that EEO cause apoptosis for MDA-MB-231 breast cancer cell line and prevent incidence (i.e., growth) of breast cancer by inhibiting fatty acid synthase (FAS) production and accumulation in adipose tissues [24].

Another in vitro study is conducted by Arif and colleagues to detect the antitumor effect of *Aloe vera* crude extract (ACE) alone and in combination with cisplatin on human breast carcinoma cell line (MCF-7) and human cervical carcinoma cell line (HeLa) [25]. **T**he cytotoxic potential of *Aloe vera* crude extract alone or in combination with cisplatin in human breast (MCF-7) and cervical (HeLa) cancer cells was studied by cell viability assay, nuclear morphological examination, and cell cycle analysis. Effects were correlated with the modulation of expression of genes involved in cell cycle regulation, apoptosis, and drug metabolism by RT-PCR. "Results showed that exposure of cells to ACE resulted in considerable loss of cell viability in a dose- and time-dependent fashion, which was found to be mediated by through the apoptotic pathway as evidenced by changes in the nuclear morphology and the distribution of cells in the different phases of the cell cycle. Interestingly, ACE did not have any significant cytotoxicity towards normal cells, thus placing it in the category of safe chemopreventive agent. Further, the effects were correlated with the downregulation of cyclin D1, CYP 1A1, and CYP 1A2 and increased expression of bax and p21 in MCF-7 and HeLa cells. In addition, a low-dose combination of ACE and cisplatin showed a combination index less than 1, indicating synergistic growth inhibition compared to the agents applied individually. In conclusion, these results signify that *Aloe vera* may be an effective antineoplastic agent to inhibit cancer cell growth and increase the therapeutic efficacy of conventional drugs like cisplatin. Thus promoting the development of plant-derived therapeutic agents appears warranted for novel cancer treatment strategies" [25].

**145**

*Plants and Cancer Treatment*

tine) [3, 4, 15].

treatment [26].

anticancer agents.

*DOI: http://dx.doi.org/10.5772/intechopen.90568*

**6. Anticancer plant-derived drugs**

About two-thirds of the anticancer treatments are extracted from plants, and these drugs are divided into several classes depending on their pharmacological effect: antimitotics [vinca alkaloids (e.g., vincristine and vinblastine), podophyllotoxins (e.g., etoposide and teniposide), and taxanes (e.g., paclitaxel, docetaxel)], topoisomerase inhibiters [Topo I (e.g., topotecan and irinotecan), Topo II (e.g., ellipticine and podophyllotoxins)], ROS inducers (e.g., EGCG2 and thymoquinone), angiogenesis inhibitors (e.g., flavopiridol), histone deacetylases (HDAC) inhibitors (e.g., sulforaphane and pomiferin), and mitotic disruptors (e.g., roscovi-

An *in vitro* study is conducted by Maram and colleagues to detect the antitumor effect of *Aloe vera* (*A. vera*) and *Calligonum* extracts on hepatocellular carcinoma (HepG2) cells. Viability, apoptosis, and DNA damage of these cells have been tested after exposure to different concentrations of the two extracts. Results showed that the extracts of these two plants could have an antitumor effect against HepG2 cells. Thus, these two plants can be promising sources for future anticancer

Nadia and colleagues conducted an *in vitro* study in which the main aim was to detect the anticancer effect of ethyl acetate extract of *Crataegus azarolus* against HCT-116 and HT-29 human colorectal cancer cell lines. Results showed that the extract demonstrated strong cytotoxic and anti-growth activities via several mechanisms. Moreover, its apoptotic effect is associated with the elevation of p21 expression but not through p53 activation. As a result of that, authors concluded that this

**7. Secondary metabolites extracted from plants used as anticancer agents**

Overtime researchers detected that plants found to be enriched with natural compounds called secondary metabolites these metabolites characterized by several points that make them effective antitumor agents. These compounds can be classified into "three main groups which are: terpenoids (polymeric isoprene derivatives and biosynthesized from acetate via the mevalonic acid pathway), phenolics (biosynthesized from shikimate pathways, containing one or more hydroxylated aromatic rings), and the extremely diverse alkaloids (nonprotein nitrogencontaining compounds, biosynthesized from amino acids such as tyrosine, with a long history in medication)" [16]. Yearly several new metabolites are extracted from plants, but limited numbers of them have been used to synthesize new potent

**8. Medicinal plant enhanced chemotherapy and radiotherapy function**

As mentioned above one of the crucial problems associated with chemotherapy drug is multidrug resistance (MDR), which happened when cancer cells become insensitive to chemotherapy treatment used for treating it [17]. The main factor that plays a role in the incidence of this phenomenon is the overexpression of ATP-binding cassette (ABC) transporters which their main function is to prevent transportation of chemotherapy drug through the biological membrane of the cell to reach its target [17]. As a result of that, many researchers are working so hard to produce and/or extract efficient and low-toxic inhibitors for ABC drug transporters from natural

compound can be used as anticancer for treating colorectal cancer [27].

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

treatment for several types of cancers [23].

and accumulation in adipose tissues [24].

proteins [21].

human body [14].

expression. Curcumin also increases vincristine chemotherapy activity in SGC7901/ VCR cell lines by suppressing ABC transporters such as P-gp, MRP1, and ABCG2

Jana and colleagues conducted in vitro study to determine the anticancer, antiproliferative, and cytotoxic effect of brassinosteroids (BRs) which are steroids extracted from plants against (MCF-7/MDA-MB-468) breast and (LNCaP/ DU-145) prostate cancer cell lines and normal cell line. Results showed that RBs significantly arrested MCF-7, MDA-MB-468, and LNCaP cells in G1 phase of the cell cycle and induced apoptosis in MDA-MB-468, LNCaP, and slightly in the DU-145 cells, without any toxic effect against normal cell lines. These results support the point that RB compounds are a promising source for anticancer drugs [22]. Another in vitro study is conducted to detect the antiproliferative and cytotoxic effect of the aqueous extract of *A. ascalonicum* against Wehi164 (mouse fibrosarcoma cells), Jurkat (human acute T-cell leukemia) and K562 (human erythroleukemia), and human umbilical vein endothelial cells (HUVEC) as a normal cell line. Results showed that the extract showed a significant antiproliferative effect against all cancer cell lines and a dose and time cytotoxic effect against them with a very low cytotoxic effect against a normal cell line. These results showed that the *Allium ascalonicum* plant is a promising source for a potent anticancer

About cancer prevention, it has been approved that several plants, herbs, and vegetables can prevent or reduce the incidence of cancer in several sites of the

An in vitro study is conducted by a group of researchers trying to detect the ability of ethyl acetate extract of onion (EEO) to cause inhibition for cancer growth and cause apoptosis in human breast cancer MDA-MB-231. Results showed that EEO cause apoptosis for MDA-MB-231 breast cancer cell line and prevent incidence (i.e., growth) of breast cancer by inhibiting fatty acid synthase (FAS) production

Another in vitro study is conducted by Arif and colleagues to detect the antitumor effect of *Aloe vera* crude extract (ACE) alone and in combination with cisplatin on human breast carcinoma cell line (MCF-7) and human cervical carcinoma cell line (HeLa) [25]. **T**he cytotoxic potential of *Aloe vera* crude extract alone or in combination with cisplatin in human breast (MCF-7) and cervical (HeLa) cancer cells was studied by cell viability assay, nuclear morphological examination, and cell cycle analysis. Effects were correlated with the modulation of expression of genes involved in cell cycle regulation, apoptosis, and drug metabolism by RT-PCR. "Results showed that exposure of cells to ACE resulted in considerable loss of cell viability in a dose- and time-dependent fashion, which was found to be mediated by through the apoptotic pathway as evidenced by changes in the nuclear morphology and the distribution of cells in the different phases of the cell cycle. Interestingly, ACE did not have any significant cytotoxicity towards normal cells, thus placing it in the category of safe chemopreventive agent. Further, the effects were correlated with the downregulation of cyclin D1, CYP 1A1, and CYP 1A2 and increased expression of bax and p21 in MCF-7 and HeLa cells. In addition, a low-dose combination of ACE and cisplatin showed a combination index less than 1, indicating synergistic growth inhibition compared to the agents applied individually. In conclusion, these results signify that *Aloe vera* may be an effective antineoplastic agent to inhibit cancer cell growth and increase the therapeutic efficacy of conventional drugs like cisplatin. Thus promoting the development of plant-derived therapeutic agents appears warranted for novel cancer treatment

**144**

strategies" [25].

### **6. Anticancer plant-derived drugs**

About two-thirds of the anticancer treatments are extracted from plants, and these drugs are divided into several classes depending on their pharmacological effect: antimitotics [vinca alkaloids (e.g., vincristine and vinblastine), podophyllotoxins (e.g., etoposide and teniposide), and taxanes (e.g., paclitaxel, docetaxel)], topoisomerase inhibiters [Topo I (e.g., topotecan and irinotecan), Topo II (e.g., ellipticine and podophyllotoxins)], ROS inducers (e.g., EGCG2 and thymoquinone), angiogenesis inhibitors (e.g., flavopiridol), histone deacetylases (HDAC) inhibitors (e.g., sulforaphane and pomiferin), and mitotic disruptors (e.g., roscovitine) [3, 4, 15].

An *in vitro* study is conducted by Maram and colleagues to detect the antitumor effect of *Aloe vera* (*A. vera*) and *Calligonum* extracts on hepatocellular carcinoma (HepG2) cells. Viability, apoptosis, and DNA damage of these cells have been tested after exposure to different concentrations of the two extracts. Results showed that the extracts of these two plants could have an antitumor effect against HepG2 cells. Thus, these two plants can be promising sources for future anticancer treatment [26].

Nadia and colleagues conducted an *in vitro* study in which the main aim was to detect the anticancer effect of ethyl acetate extract of *Crataegus azarolus* against HCT-116 and HT-29 human colorectal cancer cell lines. Results showed that the extract demonstrated strong cytotoxic and anti-growth activities via several mechanisms. Moreover, its apoptotic effect is associated with the elevation of p21 expression but not through p53 activation. As a result of that, authors concluded that this compound can be used as anticancer for treating colorectal cancer [27].

### **7. Secondary metabolites extracted from plants used as anticancer agents**

Overtime researchers detected that plants found to be enriched with natural compounds called secondary metabolites these metabolites characterized by several points that make them effective antitumor agents. These compounds can be classified into "three main groups which are: terpenoids (polymeric isoprene derivatives and biosynthesized from acetate via the mevalonic acid pathway), phenolics (biosynthesized from shikimate pathways, containing one or more hydroxylated aromatic rings), and the extremely diverse alkaloids (nonprotein nitrogencontaining compounds, biosynthesized from amino acids such as tyrosine, with a long history in medication)" [16]. Yearly several new metabolites are extracted from plants, but limited numbers of them have been used to synthesize new potent anticancer agents.

### **8. Medicinal plant enhanced chemotherapy and radiotherapy function**

As mentioned above one of the crucial problems associated with chemotherapy drug is multidrug resistance (MDR), which happened when cancer cells become insensitive to chemotherapy treatment used for treating it [17]. The main factor that plays a role in the incidence of this phenomenon is the overexpression of ATP-binding cassette (ABC) transporters which their main function is to prevent transportation of chemotherapy drug through the biological membrane of the cell to reach its target [17]. As a result of that, many researchers are working so hard to produce and/or extract efficient and low-toxic inhibitors for ABC drug transporters from natural

sources, i.e., natural products. Their main target is to restore drug sensitivity in MDR cancer cells by improving chemotherapy drug penetration, distribution, and accumulation of the drug inside the tumor cells [17]. Besides that, natural compounds extracted from plants can be used to enhance chemotherapy function in several ways, as clarified in **Table 1**.


**147**

*Plants and Cancer Treatment*

*Biophytum sensitivum (L.) DC.* 

*Mentha piperita* and *Mentha arvensis* 

*Xylopia aethiopica (Dunal) A. Rich* 

*(*Oxalidaceae*)*

*(*Lamiaceae*)*

*(*Annonaceae*)*

**Table 2.**

*DOI: http://dx.doi.org/10.5772/intechopen.90568*

**Plants (family) Radioprotective/radiosensitizing efficacy**

*Aloe arborescens Mill. (*Liliaceae*)* Radioprotective efficacy *Alstonia scholaris L. (*Apocynaceae*)* Radioprotective efficacy

*Aegle marmelos (L.) Corr. (*Rutaceae*)* Reduced decline in hemoglobin level, and leukocytes and

*Citrus sinensis (L.) Osbeck (*Rutaceae*)* Significantly counteracted UV-B-induced damage in human keratinocytes *Emblica officinalis L. (*Phyllanthaceae*)* Significantly caused depletion in lipid peroxidation and

*Grewia asiatica L. (*Malvaceae*)* Inhibited γ-radiation-induced glutathione depletion and

*Isatis indigotica Fort. (*Brassicaceae*)* Reduce the mucosal damage caused by radiation

*Panax ginseng L. (*Araliaceae*)* Prevented γ-radiation-induced DNA damage

*Olea europaea L. (*Oleaceae*)* Inhibited incidence of skin damage

*Viscum album L. (*Santalaceae*)* Palliate radiotherapy side effects

*Rosmarinus officinalis L. (*Lamiaceae*)* Prevented γ-radiation *Rubus* spp*.(*Rosaceae*)* Prevented UV radiation *Syzygium cumini L. Skeels (*Myrtaceae*)* Prevented γ-radiation *Tinospora cordifolia (*Thunb*.)* Prevented γ-radiation

*Radioprotective/radiosensitizing efficacy of plants against radiotherapy [28].*

lymphocytes counts because of radiotherapy.

Prevented γ-radiation-induced DNA damage

elevation in glutathione and catalase levels

Prevented γ-radiation-induced DNA damage

ameliorating lipid peroxidation

Regarding radiation therapy, studies found that a substantial fraction of cancers fails to response properly to radiation therapy, and for this case the use of a high dose is recommended, and this will cause incidence of major side effects (like tissue fibrosis, hair loss, myelosuppression, etc.) [28]. This will happen as a result of generation of intercellular reactive species which will cause breakdown for DNA strand and alteration in biomolecules. Moreover, the combination of radiotherapy and chemotherapy can aggravate the situation, for example, renal problems and alopecia will be detected on cancer patients treated with radiotherapy and platinum chemotherapy, while the combination with alkylating agents is found to cause infertility [28]. Therefore, researchers worked so hard to detect compounds from natural and/ or synthetic source (s) to overcome radiotherapy damage and side effects. Studies showed that some plants are radioprotectors which are capable of preventing and/or palliating radiotherapy damage and side effects. Other plants are found to be radiosensitizers which are capable of enhancing radiotherapy pharmacological effects i.e., get the desired pharmacological effect with the minimum dose, as shown in **Table 2**.

Prevented γ-radiation

**9. Nutritional approach in chemotherapy and radiotherapy**

During this century chemotherapy and radiotherapy remain as the dominant and the most effective treatments against many types of cancers. Extraordinary effort is made by the researchers to improve the efficacy of both of them. The new

#### **Table 1.**

*Various natural compounds and their effects on chemotherapy [17, 18].*


#### **Table 2.**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

**source**

Ginsenosides Ginseng Cisplatin

Catechins/theanine Green tea Doxorubicin

such as onions, apples, berries, and tea

and other citrus peels

such as onions, apples, berries, and tea

*Various natural compounds and their effects on chemotherapy [17, 18].*

as clarified in **Table 1**.

**Compound Dietary** 

Quercetin Many foods

Tangeretin Tangerine

Quercetin Many foods

sources, i.e., natural products. Their main target is to restore drug sensitivity in MDR cancer cells by improving chemotherapy drug penetration, distribution, and accumulation of the drug inside the tumor cells [17]. Besides that, natural compounds extracted from plants can be used to enhance chemotherapy function in several ways,

5-Fluorouracil

Cisplatin

Doxorubicin Busulfan Cisplatin

Genistein Soy foods Tamoxifen Attenuation of inhibitory effect

Daidzein Soy foods Tamoxifen Improvement of drug activity

Ginsenosides Ginseng Cyclophosphamide Protection against drug-

Ginsenosides Ginseng Paclitaxel Chemosensitization

Curcumin Turmeric Vinorelbine Enhancement of

**Chemotherapy drug Effect**

**Influence on treatment** 

Enhancement of drug-induced antiproliferative effect Increase in antiproliferative

chemotherapeutic efficacy

Enhancement of antitumor

Potentiation of growthinhibitory activity Synergistic antiproliferative

Increased cytotoxic effect

of tamoxifen on tumor cell

to reduce tumor burden

*Influence on side effects of* 

induced genotoxicity and apoptosis in bone marrow cells and peripheral lymphocytes

tubular cells from drug toxicity

*Influence on drug resistance*

*chemotherapy*

inhibitory effect of tamoxifen

Attenuation of tamoxifen effect on reducing of tumor burden Synergistic growth inhibition

Increase in reduction of tumor

**efficacy**

effect

activity

growth

activity

growth

Tamoxifen Complete blocking of growth-

Cisplatin Protection of normal renal

Doxorubicin Inhibition of drug efflux from tumor cells

**146**

**Table 1.**

*Radioprotective/radiosensitizing efficacy of plants against radiotherapy [28].*

Regarding radiation therapy, studies found that a substantial fraction of cancers fails to response properly to radiation therapy, and for this case the use of a high dose is recommended, and this will cause incidence of major side effects (like tissue fibrosis, hair loss, myelosuppression, etc.) [28]. This will happen as a result of generation of intercellular reactive species which will cause breakdown for DNA strand and alteration in biomolecules. Moreover, the combination of radiotherapy and chemotherapy can aggravate the situation, for example, renal problems and alopecia will be detected on cancer patients treated with radiotherapy and platinum chemotherapy, while the combination with alkylating agents is found to cause infertility [28]. Therefore, researchers worked so hard to detect compounds from natural and/ or synthetic source (s) to overcome radiotherapy damage and side effects. Studies showed that some plants are radioprotectors which are capable of preventing and/or palliating radiotherapy damage and side effects. Other plants are found to be radiosensitizers which are capable of enhancing radiotherapy pharmacological effects i.e., get the desired pharmacological effect with the minimum dose, as shown in **Table 2**.

### **9. Nutritional approach in chemotherapy and radiotherapy**

During this century chemotherapy and radiotherapy remain as the dominant and the most effective treatments against many types of cancers. Extraordinary effort is made by the researchers to improve the efficacy of both of them. The new vision for doing that is by using natural products (supplements) in concurrent with them [18, 29].

Besides, these supplements will significantly reduce the incidence of many side effects like "oral mucositis, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, hematopoietic system injury, cardiotoxicity, and neurotoxicity" that can be caused by the use of the pharmacological treatments, and example for these natural supplements are ginseng extract, grape seed extract, and curcumin [18, 30].

Moreover, nutritional supplement can also help in increasing cancer cell apoptosis, reducing multidrug resistance, increasing drug penetration and its concentration inside cancer cells, and reducing incidence of weight loss, malnutrition, and severity of comorbidities. At the same time, they can significantly improve cancer patients' quality of life [18]. As a result of that, clinicians encouraged to administer nutritional supplement in combination with chemotherapy, rather than giving them separately [18].

One of the most important benefits that can be obtained by combining nutritional supplement with chemotherapy is reducing the incidence of drug resistance by inhibiting ABC transporters [example P-glycoprotein (P-gp) and multidrug resistance proteins (MRP-s)] [18]. Currently no synthetic material is found to be efficient and safe for multidrug resistance, but some novel compounds extracted from natural products can help in some ways to solve this crucial problem [18].

An in vitro study is conducted to determine the antiproliferative and apoptotic effect of *B. serrata* plant methanolic extract as a monotherapy and in combination with doxorubicin (DOX) chemotherapy against hepatocellular carcinoma cell lines (HepG2) and (Hep3B). The results showed that the extract of the plant inhibited the proliferation of both cancer cell lines (HepG2 and Hep3B) with IC50 values 21.21 ± 0.92 and 18.65 ± 0.71 g/mL, respectively. About DOX it caused an inhibition for proliferation of both cancer cell lines at IC50 values 1.06 ± 0.04 and 1.92 ± 0.09 g/ML, respectively, while when the extract is used in combination with DOX, results showed that there was a synergistic effect against both cancer cell lines with combination index (CI) of DOX and *B. serrata* extract of 0.53 ± 0.03 to 0.79 ± 0.02. Besides, results showed that the use of the extract alone and in combination with Dox significantly stimulated the activity of caspase-3 and the activation in combination with Dox was higher. A similar result also gotten about the use of the extract with Dox significantly increased the expression of *TNF-* and IL-6 and reduced the anti-apoptotic protein level which is *NF-B*. Moreover, the use of the extract showed a significant reduction in liver enzymes SGOT, SGPT, and ALP which have been elevated as a result of the use of Dox alone, i.e., the extract significantly helped in reducing liver toxicity. Also the extract leaded to restored albumin protein level which has been decreased as a result of Dox use. Moreover, the use of the extract with Dox chemotherapy significantly helps in preserving the histological architecture of the liver, which showed a significant change among group of rats receiving Dox chemotherapy alone. All these points confirmed that the use of the extract in combination with Dox will significantly help in improving treatment of hepatocellular cancer and reducing side effects of Dox [31].

**149**

**Author details**

Bassam Hassan

Department of Pharmacy, AL-Rafidain University College, Baghdad, Iraq

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: bassamsunny@yahoo.com

provided the original work is properly cited.

*Plants and Cancer Treatment*

*DOI: http://dx.doi.org/10.5772/intechopen.90568*

*Plants and Cancer Treatment DOI: http://dx.doi.org/10.5772/intechopen.90568*

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

them [18, 29].

separately [18].

vision for doing that is by using natural products (supplements) in concurrent with

Besides, these supplements will significantly reduce the incidence of many side effects like "oral mucositis, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, hematopoietic system injury, cardiotoxicity, and neurotoxicity" that can be caused by the use of the pharmacological treatments, and example for these natural supple-

Moreover, nutritional supplement can also help in increasing cancer cell apoptosis, reducing multidrug resistance, increasing drug penetration and its concentration inside cancer cells, and reducing incidence of weight loss, malnutrition, and severity of comorbidities. At the same time, they can significantly improve cancer patients' quality of life [18]. As a result of that, clinicians encouraged to administer nutritional supplement in combination with chemotherapy, rather than giving them

One of the most important benefits that can be obtained by combining nutritional supplement with chemotherapy is reducing the incidence of drug resistance by inhibiting ABC transporters [example P-glycoprotein (P-gp) and multidrug resistance proteins (MRP-s)] [18]. Currently no synthetic material is found to be efficient and safe for multidrug resistance, but some novel compounds extracted from natural products can help in some ways to solve this crucial problem [18]. An in vitro study is conducted to determine the antiproliferative and apoptotic effect of *B. serrata* plant methanolic extract as a monotherapy and in combination with doxorubicin (DOX) chemotherapy against hepatocellular carcinoma cell lines (HepG2) and (Hep3B). The results showed that the extract of the plant inhibited the proliferation of both cancer cell lines (HepG2 and Hep3B) with IC50 values 21.21 ± 0.92 and 18.65 ± 0.71 g/mL, respectively. About DOX it caused an inhibition for proliferation of both cancer cell lines at IC50 values 1.06 ± 0.04 and 1.92 ± 0.09 g/ML, respectively, while when the extract is used in combination with DOX, results showed that there was a synergistic effect against both cancer cell lines with combination index (CI) of DOX and *B. serrata* extract of 0.53 ± 0.03 to 0.79 ± 0.02. Besides, results showed that the use of the extract alone and in combination with Dox significantly stimulated the activity of caspase-3 and the activation in combination with Dox was higher. A similar result also gotten about the use of the extract with Dox significantly increased the expression of *TNF-* and IL-6 and reduced the anti-apoptotic protein level which is *NF-B*. Moreover, the use of the extract showed a significant reduction in liver enzymes SGOT, SGPT, and ALP which have been elevated as a result of the use of Dox alone, i.e., the extract significantly helped in reducing liver toxicity. Also the extract leaded to restored albumin protein level which has been decreased as a result of Dox use. Moreover, the use of the extract with Dox chemotherapy significantly helps in preserving the histological architecture of the liver, which showed a significant change among group of rats receiving Dox chemotherapy alone. All these points confirmed that the use of the extract in combination with Dox will significantly help in improving treatment of

ments are ginseng extract, grape seed extract, and curcumin [18, 30].

hepatocellular cancer and reducing side effects of Dox [31].

**148**

### **Author details**

Bassam Hassan Department of Pharmacy, AL-Rafidain University College, Baghdad, Iraq

\*Address all correspondence to: bassamsunny@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

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[3] Dolan S. Anaemia. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London, England: Churchill Livingstone, Elsevier; 2005

[4] Henry L. Malnutrition. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London, England: Churchill Livingstone, Elsevier; 2005

[5] Sitamvaram R. Gastrointestinal effects. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London, England: Churchill Livingstone, Elsevier; 2005

[6] Stephens M. Nausea and vomiting. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London, England: Churchill Livingstone, Elsevier; 2005

[7] Weir-Hughes D. Foreword. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London: Elsevier/ Churchill Livingstone; 2005

[8] Scurr M, Judson I, Root T. Combination chemotherapy and chemotherapy principles. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London: Elsevier/ Churchill Livingstone; 2005

[9] Kelland LR. Cancer cell biology, drug action and resistance. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London: Elsevier/ Churchill Livingstone; 2005

[10] Rizzo T, Cloos R. Chemotherapy. In: Thackery E, editor. The Gale Encyclopedia of Cancer. Detroit: Gale Group; 2002

[11] Abrams AC. Drugs used in oncologic disorders. In: Repchinsky C, editor. Clinical Drug Therapy. 36th ed. Ontario: Canadian Pharmacists Association; 2001

[12] Koda-Kimble LYY, Wayne A, Kradjan BJG, Brain KA, Robin LC. Applied therapeutics the clinical use of drugs. In: Troy D, editor. Handbook of Applied Therapeutics. Philadelphia: Lippincott Williams & Wilkins; 2002

[13] Shabani A. A review of anticancer properties of herbal medicines. Journal of Pharmaceutical Care and Health Systems. 2016;**3**:2

[14] Ahmad R, Ahmad N, Naqvi AA, Shehzad A, Al-Ghamdi MS. Role of traditional Islamic and Arabic plants in cancer therapy. Journal of Traditional and Complementary Medicine. 2016;**7**(2):195-204

[15] Zaid H, Silbermann M, Ben-Arye E, Saad B. Greco-Arab and Islamic herbalderived anticancer modalities: From tradition to molecular mechanisms. Evidence-based Complementary and Alternative Medicine. 2012;**2012**:1-14

[16] Seca AM, Pinto DC. Plant secondary metabolites as anticancer agents: Successes in clinical trials and therapeutic application. International Journal of Molecular Sciences. 2018;**19**(263):1-22

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*Plants and Cancer Treatment*

2011;**12**(4):609-620

2012;**2012**:1-11

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[25] Hussain A, Sharma C, Khan S, Shah K, Haque S. Aloe vera inhibits proliferation of human breast and cervical cancer cells and acts synergistically with cisplatin. Asian Pacific Journal of Cancer Prevention.

[26] Shalabi M, Khilo K, Zakaria MM, Elsebaei MG, Abdo W, Awadin W. Anticancer activity of *Aloe vera* and *Calligonum comosum* extracts separately on hepatocellular carcinoma cells. Asian Pacific Journal of Tropical Biomedicine.

[27] Mustapha N, Pinon A, Limami Y, Simon A, Ghedira K, Hennebelle T, et al. Crataegus azarolus leaves induce antiproliferative activity, cell cycle arrest, and apoptosis in human HT-29 and HCT-116 colorectal cancer cells. Journal of Cellular Biochemistry.

2015;**16**(7):2939-2946

2015;**5**(5):375-381

2016;**117**(5):1262-1272

[28] Hazra B, Ghosh S, Kumar A, Pandey BN. The prospective role of plant products in radiotherapy of cancer: A current overview. Frontiers in

Pharmacology. 2012;**2**(94):1-13

health products and cancer

[30] Zhang Q-Y, Wang F-X, Jia K-K, Kong L-D. Natural product interventions for chemotherapy and radiotherapy-induced side effects. Frontiers in Pharmacology. 2018;**9**:1-25

[31] Mazzio EA, Lewis CA,

2017;**14**:409-425

[29] Oneschuk D, Younus J. Natural

chemotherapy and radiation therapy. Oncology Reviews. 2008;**1**:233-242

Soliman KFA. Transcriptomic profiling of MDA-MB-231 cells exposed to *Boswellia Serrata* and 3-O-acetyl-Β-Boswellic acid; ER/UPR mediated programmed cell death. Cancer Genomics and Proteomics.

[17] Wu CP, Ohnuma S, Ambudkar SV. Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Current Pharmaceutical Biotechnology.

[18] Sak K. Chemotherapy and dietary phytochemical agents.

[19] Lichota A, Gwozdzinski K. Anticancer activity of natural compounds from plant and marine environment. International Journal of Molecular Sciences. 2018;**19**:1-38

[20] Desai AG, Qazi GN, Ganju RK, El-Tamer M, Singh J, Saxena AK, et al. Medicinal plants and cancer chemoprevention. Current Drug Metabolism. 2008;**9**(7):581-591

[21] Aung TN, Zhipeng Q, Daniel Kortschak R, Adelson DL. Understanding the effectiveness of natural compound mixtures in cancer through their molecular mode of action. International Journal of Molecular Sciences. 2017;**18**(656):1-20

[22] Malıkova J, Swaczynova J, Kolar Z, Strnad M. Anticancer and antiprolifer-ative activity of natural brassinosteroids. Phytochemistry.

[23] Mohammadi-Motlagh H-R, Mostafaie A, Mansouri K. Anticancer and anti-inflammatory activities of shallot (*Allium ascalonicum*) extract. Archives of Medical Science.

[24] Wang Y, Tian W-X, M X-F. Inhibitory effects of onion (*Allium cepa* L.) extract on proliferation of cancer cells and adipocytes via inhibiting fatty acid synthase. The Asian Pacific Journal of Cancer Prevention.

2008;**69**:418-426

2011;**7**(1):38-44

2012;**13**(11):5573-5579

Chemotherapy Research and Practice.

#### *Plants and Cancer Treatment DOI: http://dx.doi.org/10.5772/intechopen.90568*

[17] Wu CP, Ohnuma S, Ambudkar SV. Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Current Pharmaceutical Biotechnology. 2011;**12**(4):609-620

[18] Sak K. Chemotherapy and dietary phytochemical agents. Chemotherapy Research and Practice. 2012;**2012**:1-11

[19] Lichota A, Gwozdzinski K. Anticancer activity of natural compounds from plant and marine environment. International Journal of Molecular Sciences. 2018;**19**:1-38

[20] Desai AG, Qazi GN, Ganju RK, El-Tamer M, Singh J, Saxena AK, et al. Medicinal plants and cancer chemoprevention. Current Drug Metabolism. 2008;**9**(7):581-591

[21] Aung TN, Zhipeng Q, Daniel Kortschak R, Adelson DL. Understanding the effectiveness of natural compound mixtures in cancer through their molecular mode of action. International Journal of Molecular Sciences. 2017;**18**(656):1-20

[22] Malıkova J, Swaczynova J, Kolar Z, Strnad M. Anticancer and antiprolifer-ative activity of natural brassinosteroids. Phytochemistry. 2008;**69**:418-426

[23] Mohammadi-Motlagh H-R, Mostafaie A, Mansouri K. Anticancer and anti-inflammatory activities of shallot (*Allium ascalonicum*) extract. Archives of Medical Science. 2011;**7**(1):38-44

[24] Wang Y, Tian W-X, M X-F. Inhibitory effects of onion (*Allium cepa* L.) extract on proliferation of cancer cells and adipocytes via inhibiting fatty acid synthase. The Asian Pacific Journal of Cancer Prevention. 2012;**13**(11):5573-5579

[25] Hussain A, Sharma C, Khan S, Shah K, Haque S. Aloe vera inhibits proliferation of human breast and cervical cancer cells and acts synergistically with cisplatin. Asian Pacific Journal of Cancer Prevention. 2015;**16**(7):2939-2946

[26] Shalabi M, Khilo K, Zakaria MM, Elsebaei MG, Abdo W, Awadin W. Anticancer activity of *Aloe vera* and *Calligonum comosum* extracts separately on hepatocellular carcinoma cells. Asian Pacific Journal of Tropical Biomedicine. 2015;**5**(5):375-381

[27] Mustapha N, Pinon A, Limami Y, Simon A, Ghedira K, Hennebelle T, et al. Crataegus azarolus leaves induce antiproliferative activity, cell cycle arrest, and apoptosis in human HT-29 and HCT-116 colorectal cancer cells. Journal of Cellular Biochemistry. 2016;**117**(5):1262-1272

[28] Hazra B, Ghosh S, Kumar A, Pandey BN. The prospective role of plant products in radiotherapy of cancer: A current overview. Frontiers in Pharmacology. 2012;**2**(94):1-13

[29] Oneschuk D, Younus J. Natural health products and cancer chemotherapy and radiation therapy. Oncology Reviews. 2008;**1**:233-242

[30] Zhang Q-Y, Wang F-X, Jia K-K, Kong L-D. Natural product interventions for chemotherapy and radiotherapy-induced side effects. Frontiers in Pharmacology. 2018;**9**:1-25

[31] Mazzio EA, Lewis CA, Soliman KFA. Transcriptomic profiling of MDA-MB-231 cells exposed to *Boswellia Serrata* and 3-O-acetyl-Β-Boswellic acid; ER/UPR mediated programmed cell death. Cancer Genomics and Proteomics. 2017;**14**:409-425

**150**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

[9] Kelland LR. Cancer cell biology, drug action and resistance. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London: Elsevier/ Churchill Livingstone; 2005

[10] Rizzo T, Cloos R. Chemotherapy. In: Thackery E, editor. The Gale Encyclopedia of Cancer. Detroit: Gale

[11] Abrams AC. Drugs used in oncologic disorders. In: Repchinsky C, editor. Clinical Drug Therapy. 36th ed. Ontario: Canadian Pharmacists Association;

[12] Koda-Kimble LYY, Wayne A, Kradjan BJG, Brain KA, Robin LC. Applied therapeutics the clinical use of drugs. In: Troy D, editor. Handbook of Applied Therapeutics. Philadelphia: Lippincott Williams & Wilkins; 2002

[13] Shabani A. A review of anticancer properties of herbal medicines. Journal of Pharmaceutical Care and Health

[14] Ahmad R, Ahmad N, Naqvi AA, Shehzad A, Al-Ghamdi MS. Role of traditional Islamic and Arabic plants in cancer therapy. Journal of Traditional and Complementary Medicine.

[15] Zaid H, Silbermann M, Ben-Arye E, Saad B. Greco-Arab and Islamic herbalderived anticancer modalities: From tradition to molecular mechanisms. Evidence-based Complementary and Alternative Medicine. 2012;**2012**:1-14

[16] Seca AM, Pinto DC. Plant secondary metabolites as anticancer agents: Successes in clinical trials and therapeutic application. International

Journal of Molecular Sciences.

2018;**19**(263):1-22

Systems. 2016;**3**:2

2016;**7**(2):195-204

Group; 2002

2001

[1] Carson-Dewitt R. Cancer. In:

Group; 2002

**References**

2002

Longe JL, editor. The Gale Encyclopedia of Medicine. Farmington Hills: Gale

[2] Markman M. Principles of cancer screening. In: Aziz K, Wu GY, editors. Cancer Screening: A Practical Guide for Physicians. New Jersey: Humana Press;

[3] Dolan S. Anaemia. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London, England: Churchill Livingstone, Elsevier; 2005

Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London, England: Churchill Livingstone, Elsevier; 2005

[5] Sitamvaram R. Gastrointestinal effects. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London, England: Churchill Livingstone,

[6] Stephens M. Nausea and vomiting. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London, England: Churchill Livingstone,

[7] Weir-Hughes D. Foreword. In: Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London: Elsevier/ Churchill Livingstone; 2005

[8] Scurr M, Judson I, Root T. Combination chemotherapy and chemotherapy principles. In:

Brighton D, Wood M, editors. The Royal Marsden Hospital Handbook of Cancer Chemotherapy. London: Elsevier/ Churchill Livingstone; 2005

Elsevier; 2005

Elsevier; 2005

[4] Henry L. Malnutrition. In:

**153**

**Chapter 10**

**Abstract**

**1. Introduction**

*Pranab Behari Mazumder*

Herbal Remedies for Breast Cancer

Prevention and Treatment

phytocompounds to report their potential chemotherapeutic role.

**Keywords:** herbal remedies, phytochemicals, phytoestrogens, breast cancer

According to World Health Organization (WHO), cancer is the second leading cause of death after cardiovascular diseases and a growing health issue globally. Breast cancer is the most commonly diagnosed type of cancer among females accounting for approximately one-quarter of cancers in females globally. Great research efforts are in place to understand the cause of breast cancer onset, to identify the critical molecular mechanism of its progression, and to define new ways of treating it with lower and limited toxicity. These efforts are certainly encouraging since overall survival has greatly improved in several breast cancer types during the last decade. Since 1990, mortality rates of breast cancer have reduced significantly by 25%, this is at least in part due to the significant improvement in its treatment [1]. Treatment of cancer mainly relies on chemotherapy that uses cytotoxic agents for killing cancer cells. However, these agents or drugs affect both cancer cells as well as healthy cells, causing an array of side effects during the therapy or after the therapy. To overcome these problems, current research is emphasized to explore herbal remedies that selectively targets cancer cells. Besides this, unlike other

*Yahyea Baktiar Laskar, Romen Meitei Lourembam and* 

Breast cancer is among the most common type of cancer in women around the globe. Prevention of breast cancer is better than its treatment. Because of the molecular variation and complexity underlying breast cancer occurrence, its treatment by using chemotherapy and/or radiotherapy is very complicated and often leads to undesirable side effects. Plants and their extracts have been used for centuries for the treatment of almost every disease and breast cancer is not an exception. Herbal products can be trusted for cancer treatment because of their low toxicity. Besides, herbal remedies are easily accepted by the majority of woman suffering from breast cancer because of their easy availability and affordability. In the last decade, a large number of plants and their compounds were reported to show promising anticancerous effects against breast cancer cells in both *in vivo* and *in vitro* models. However, their beneficial effects on breast cancer treatment are still doubtful due to the lack of randomized clinical trials. This chapter is dedicated to reporting the potential of some herbal products for the prevention and/or treatment of breast cancer. Besides, it focused on the anticarcinogenic mechanism of those

### **Chapter 10**

## Herbal Remedies for Breast Cancer Prevention and Treatment

*Yahyea Baktiar Laskar, Romen Meitei Lourembam and Pranab Behari Mazumder*

#### **Abstract**

Breast cancer is among the most common type of cancer in women around the globe. Prevention of breast cancer is better than its treatment. Because of the molecular variation and complexity underlying breast cancer occurrence, its treatment by using chemotherapy and/or radiotherapy is very complicated and often leads to undesirable side effects. Plants and their extracts have been used for centuries for the treatment of almost every disease and breast cancer is not an exception. Herbal products can be trusted for cancer treatment because of their low toxicity. Besides, herbal remedies are easily accepted by the majority of woman suffering from breast cancer because of their easy availability and affordability. In the last decade, a large number of plants and their compounds were reported to show promising anticancerous effects against breast cancer cells in both *in vivo* and *in vitro* models. However, their beneficial effects on breast cancer treatment are still doubtful due to the lack of randomized clinical trials. This chapter is dedicated to reporting the potential of some herbal products for the prevention and/or treatment of breast cancer. Besides, it focused on the anticarcinogenic mechanism of those phytocompounds to report their potential chemotherapeutic role.

**Keywords:** herbal remedies, phytochemicals, phytoestrogens, breast cancer

#### **1. Introduction**

According to World Health Organization (WHO), cancer is the second leading cause of death after cardiovascular diseases and a growing health issue globally. Breast cancer is the most commonly diagnosed type of cancer among females accounting for approximately one-quarter of cancers in females globally. Great research efforts are in place to understand the cause of breast cancer onset, to identify the critical molecular mechanism of its progression, and to define new ways of treating it with lower and limited toxicity. These efforts are certainly encouraging since overall survival has greatly improved in several breast cancer types during the last decade. Since 1990, mortality rates of breast cancer have reduced significantly by 25%, this is at least in part due to the significant improvement in its treatment [1]. Treatment of cancer mainly relies on chemotherapy that uses cytotoxic agents for killing cancer cells. However, these agents or drugs affect both cancer cells as well as healthy cells, causing an array of side effects during the therapy or after the therapy. To overcome these problems, current research is emphasized to explore herbal remedies that selectively targets cancer cells. Besides this, unlike other

cancer types, breast cancer has diverse genetic mutations that affect several pathways [2]. These complexities aid to distinct pathological types with different clinical outcomes [3]. Therefore, response to a certain chemotherapeutic drug may differ in different patients and lack of proper treatment plan may increase the toxicity furthermore. One of the encouraging approaches to overcome drug toxicity is to look for alternative medicines that have less or selective toxicity toward cancer cells [4]. In recent years, many studies have demonstrated selective cytotoxicity of a variety of herbal compounds that can be used as potential chemotherapeutics [4]. Meanwhile, diverse herbal products were reported to prevent and/or palliate the side effects of treatment, improve quality of life, and reduce stress. However, the usefulness of herbal remedies for breast cancer prevention and/or treatment is still ambiguous due to the lack of randomized clinical trials. These objectives will be achievable only if the herbal compounds that showed promising anticancer activity can be successfully transferred to clinical trials.

### **2. Current scenario and future burden of breast cancer**

Cancer of the breast is among the most frequently diagnosed cancer and the leading cause of cancer-related deaths in females globally. According to International Agency for Research on Cancer (IARC's) Globocan data on 2018, breast cancer caused 0.62 million deaths in 2018 and another 2.08 million new cases were identified, which is 11.6% of all cancer types recorded [5]. At the current rate, the number of incident cases is expected to rise to 3.05 million, and the mortality troll is expected to rise to a nerve-racking 6.99 million by 2040 [6]. Approximately 1 in 10 women is diagnosed with breast cancer at some time in their lives [3].

Epidemiological observation shows that the incidence of breast cancer is continuously raising in both industrialized and developing countries [7]. Breast cancer is a disease largely triggered by environmental and lifestyle factors than genetic, which is believed to be responsible for only 10–15% of all breast cancer cases [8]. Various risk factors like age (>50), family history of breast cancer, woman's reproductive history such as early menarche, nulliparity or late pregnancy, and late menopause mainly aid to breast cancer onset [9]. In addition, prolonged use of oral contraceptive and hormone replacement therapy are also known risk factors of this disease among postmenopausal women [10].

### **3. Molecular feature of breast cancer occurrence, progression, and treatment**

The onset of cancer is a result of several sequential molecular events. Most common of them is a mutation in a DNA molecule that codes for a protein that either triggers cell division, proliferation, and growth or that signals termination of all these molecular events [11]. Therefore, damage to DNA or a protein that regulates cell cycle may lead to uncontrolled division and growth of cells, the condition is cancer. It is a hyperproliferative disease that involves molecular alteration resulting in apoptosis dysregulation, proliferation, angiogenesis, and metastasis [12].

Breast cancer is one of the commonest types of cancer and characterized by distinct pathological types with different clinical outcomes. It has different stages that arise from ductal hyperproliferation, which changes into ductal carcinoma *in situ* (DCIS), invasive carcinoma, and metastatic stage. In addition, based on the molecular mechanism of occurrence, breast cancer can be divided into estrogen receptor (ERα) and progesterone receptor (PR) expression and amplification

**155**

stages of breast cancer [23].

*Herbal Remedies for Breast Cancer Prevention and Treatment*

of human epidermal growth factor receptor (HER2), also known as epidermal growth factor receptor 2 (ErbB2) [3]. Breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are the two most important genes that code the proteins BRCA-1 and BRCA-2, which play a key role in DNA damage repair and in maintaining genomic stability [3]. Mutation in these genes leads to 15–20 fold increases the risk of breast cancer occurrence [13]. Additionally, tumor suppressor TP53 is another important gene that codes for the protein p53 that plays a major role in the regulation of cell cycle and in apoptosis induction. Mutation in the TP53 gene increases the risk of breast cancer as well as other cancer types. Breast cancer cell survival, proliferation, motility, and cell metabolism are controlled by various signaling cascades. In around 70% of breast cancers, the phosphatidylinositol 3-kinase (PI3K)/ AKT pathway has shown to be mutated [14]. Other frequently mutated signaling cascades in breast cancer are Janus kinase (JAK)/signal transducer, activators of transcription (STAT), and nuclear factor κβ (NF-κβ) pathways [3]. Classification of breast cancer based on the molecular expression has therapeutic implication as it helps in deciding the treatment plan. Based on the relative expression of the above markers, patients either receives hormonal therapy or chemo/targeted therapies. The most promising way of dealing with cancer is to interfere with modulation stages of carcinogenesis—initiation, promotion, and progression as well as altering

Breast cancer therapeutics include drugs that protect genomic stability by preventing DNA damage, inhibit the cell cycle by disrupting cellular integrity or by inducing apoptotic cell death, and block certain pathways that are responsible for abnormal cell growth (**Table 1**). Majority of breast cancer cases express the estrogen hormone receptor, which helps the cancer cells to proliferate rapidly by the growth-promoting effects of circulatory estrogens [17]. Therefore, current therapies are targeted at abrogating estrogen dependence for estrogen receptor (ER)-positive breast cancers [17]. One of the successful and efficient approaches is the employment of a selective estrogen receptor modulator (SERM) like tamoxifen, which binds to the ER that induces a conformational change in the receptor resulting in obstruction of estrogenic expression [18, 19]. However, tamoxifen like SERMs exhibits many notable side effects including—secondary cancer, cardiovascular diseases by their estrogenic activity in other tissues and organs. The efficiency of tamoxifen is challenged by the development of highly potent third-generation aromatase inhibitors (AIs) that represents a promising approach in endocrine therapy of breast cancer [20]. The aromatase inhibitor drugs like anastrozole and letrozole reduce estrogen production by competitive inhibition of the enzyme aromatase, although the long-term health effects of AIs are doubtful [21]. Another effective strategy in breast cancer treatment is the implementation of a growth factor inhibitor. One of the first identified targets of these growth inhibitors was the epidermal growth factor receptor (EGFR) that plays a vital role in the survival of cancer cells and developing multidrug resistance [22]. The effectiveness of the small molecule EGFR tyrosine kinase inhibitor like gefitinib is highly appreciated for the treatment of breast cancer; however, it failed to produce notable improvement in advance

Approximately 20% of breast cancer cases show overexpression of the HER2 that results in aggressive disease and reduced survival [17]. In present, trastuzumab and lapatinib are the only marketed drugs used to inhibit the HER2-mediated growth and proliferation signaling [17]. Other than this, enzyme-mediated DNA damage is an effective approach used in cancer chemotherapy. Doxorubicin, an anthracycline drug, binds with DNA by intercalation with base pairs, which results in an elevated level of DNA-topoisomerase II covalent complexes inhibiting topoisomerase II activity [24]. Other anticancer drugs inhibit mitosis by interrupting the

*DOI: http://dx.doi.org/10.5772/intechopen.89669*

the carcinogenesis signaling pathways [15, 16].

#### *Herbal Remedies for Breast Cancer Prevention and Treatment DOI: http://dx.doi.org/10.5772/intechopen.89669*

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

can be successfully transferred to clinical trials.

among postmenopausal women [10].

**and treatment**

**2. Current scenario and future burden of breast cancer**

Cancer of the breast is among the most frequently diagnosed cancer and the leading cause of cancer-related deaths in females globally. According to International Agency for Research on Cancer (IARC's) Globocan data on 2018, breast cancer caused 0.62 million deaths in 2018 and another 2.08 million new cases were identified, which is 11.6% of all cancer types recorded [5]. At the current rate, the number of incident cases is expected to rise to 3.05 million, and the mortality troll is expected to rise to a nerve-racking 6.99 million by 2040 [6]. Approximately 1 in 10 women is diagnosed with breast cancer at some time in their lives [3].

Epidemiological observation shows that the incidence of breast cancer is continuously raising in both industrialized and developing countries [7]. Breast cancer is a disease largely triggered by environmental and lifestyle factors than genetic, which is believed to be responsible for only 10–15% of all breast cancer cases [8]. Various risk factors like age (>50), family history of breast cancer, woman's reproductive history such as early menarche, nulliparity or late pregnancy, and late menopause mainly aid to breast cancer onset [9]. In addition, prolonged use of oral contraceptive and hormone replacement therapy are also known risk factors of this disease

The onset of cancer is a result of several sequential molecular events. Most common of them is a mutation in a DNA molecule that codes for a protein that either triggers cell division, proliferation, and growth or that signals termination of all these molecular events [11]. Therefore, damage to DNA or a protein that regulates cell cycle may lead to uncontrolled division and growth of cells, the condition is cancer. It is a hyperproliferative disease that involves molecular alteration resulting

**3. Molecular feature of breast cancer occurrence, progression,** 

in apoptosis dysregulation, proliferation, angiogenesis, and metastasis [12]. Breast cancer is one of the commonest types of cancer and characterized by distinct pathological types with different clinical outcomes. It has different stages that arise from ductal hyperproliferation, which changes into ductal carcinoma *in situ* (DCIS), invasive carcinoma, and metastatic stage. In addition, based on the molecular mechanism of occurrence, breast cancer can be divided into estrogen receptor (ERα) and progesterone receptor (PR) expression and amplification

cancer types, breast cancer has diverse genetic mutations that affect several pathways [2]. These complexities aid to distinct pathological types with different clinical outcomes [3]. Therefore, response to a certain chemotherapeutic drug may differ in different patients and lack of proper treatment plan may increase the toxicity furthermore. One of the encouraging approaches to overcome drug toxicity is to look for alternative medicines that have less or selective toxicity toward cancer cells [4]. In recent years, many studies have demonstrated selective cytotoxicity of a variety of herbal compounds that can be used as potential chemotherapeutics [4]. Meanwhile, diverse herbal products were reported to prevent and/or palliate the side effects of treatment, improve quality of life, and reduce stress. However, the usefulness of herbal remedies for breast cancer prevention and/or treatment is still ambiguous due to the lack of randomized clinical trials. These objectives will be achievable only if the herbal compounds that showed promising anticancer activity

**154**

of human epidermal growth factor receptor (HER2), also known as epidermal growth factor receptor 2 (ErbB2) [3]. Breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are the two most important genes that code the proteins BRCA-1 and BRCA-2, which play a key role in DNA damage repair and in maintaining genomic stability [3]. Mutation in these genes leads to 15–20 fold increases the risk of breast cancer occurrence [13]. Additionally, tumor suppressor TP53 is another important gene that codes for the protein p53 that plays a major role in the regulation of cell cycle and in apoptosis induction. Mutation in the TP53 gene increases the risk of breast cancer as well as other cancer types. Breast cancer cell survival, proliferation, motility, and cell metabolism are controlled by various signaling cascades. In around 70% of breast cancers, the phosphatidylinositol 3-kinase (PI3K)/ AKT pathway has shown to be mutated [14]. Other frequently mutated signaling cascades in breast cancer are Janus kinase (JAK)/signal transducer, activators of transcription (STAT), and nuclear factor κβ (NF-κβ) pathways [3]. Classification of breast cancer based on the molecular expression has therapeutic implication as it helps in deciding the treatment plan. Based on the relative expression of the above markers, patients either receives hormonal therapy or chemo/targeted therapies. The most promising way of dealing with cancer is to interfere with modulation stages of carcinogenesis—initiation, promotion, and progression as well as altering the carcinogenesis signaling pathways [15, 16].

Breast cancer therapeutics include drugs that protect genomic stability by preventing DNA damage, inhibit the cell cycle by disrupting cellular integrity or by inducing apoptotic cell death, and block certain pathways that are responsible for abnormal cell growth (**Table 1**). Majority of breast cancer cases express the estrogen hormone receptor, which helps the cancer cells to proliferate rapidly by the growth-promoting effects of circulatory estrogens [17]. Therefore, current therapies are targeted at abrogating estrogen dependence for estrogen receptor (ER)-positive breast cancers [17]. One of the successful and efficient approaches is the employment of a selective estrogen receptor modulator (SERM) like tamoxifen, which binds to the ER that induces a conformational change in the receptor resulting in obstruction of estrogenic expression [18, 19]. However, tamoxifen like SERMs exhibits many notable side effects including—secondary cancer, cardiovascular diseases by their estrogenic activity in other tissues and organs. The efficiency of tamoxifen is challenged by the development of highly potent third-generation aromatase inhibitors (AIs) that represents a promising approach in endocrine therapy of breast cancer [20]. The aromatase inhibitor drugs like anastrozole and letrozole reduce estrogen production by competitive inhibition of the enzyme aromatase, although the long-term health effects of AIs are doubtful [21]. Another effective strategy in breast cancer treatment is the implementation of a growth factor inhibitor. One of the first identified targets of these growth inhibitors was the epidermal growth factor receptor (EGFR) that plays a vital role in the survival of cancer cells and developing multidrug resistance [22]. The effectiveness of the small molecule EGFR tyrosine kinase inhibitor like gefitinib is highly appreciated for the treatment of breast cancer; however, it failed to produce notable improvement in advance stages of breast cancer [23].

Approximately 20% of breast cancer cases show overexpression of the HER2 that results in aggressive disease and reduced survival [17]. In present, trastuzumab and lapatinib are the only marketed drugs used to inhibit the HER2-mediated growth and proliferation signaling [17]. Other than this, enzyme-mediated DNA damage is an effective approach used in cancer chemotherapy. Doxorubicin, an anthracycline drug, binds with DNA by intercalation with base pairs, which results in an elevated level of DNA-topoisomerase II covalent complexes inhibiting topoisomerase II activity [24]. Other anticancer drugs inhibit mitosis by interrupting the


#### **Table 1.**

*Commonly used breast cancer chemotherapeutic drugs, their targets, and mechanism of action [26].*

microtubule stability, hence blocking the transition from metaphase to anaphase [25]. Subsequently, the cell undergoes mitotic arrest or programmed cell death (apoptosis). For instance, vincristine and vinorelbine inhibit the polymerization of microtubules by binding to either the vinca domain or taxoid-binding domain that interferes between β- and α-subunit of tubulin [25]. On the other hand, microtubulestabilizing drugs like paclitaxel hyperstabilizes the microtubule assembly by binding to the inner surface of the microtubule at a taxoid-binding site on β-tubulin resulting in mitotic arrest in the cell [25]. All these strategies helped in reducing mortality due to breast cancer and increased the survival rate; however, they appear with certain side effects that may be either low and short term or high and life threatening.

#### **4. Chemotherapeutic-associated toxicity in breast cancer treatment**

The role of chemotherapy in curing cancer is still doubtful [27]. Even it decreases the risk of recurrence and helps the patient to live longer with improved quality of life in case of metastatic breast cancer. But its use associated with certain risk factors or side effects—some of the side effects are short term and minor, whereas others may become more serious and life threatening [27]. **Table 2** describes a few commonly used chemotherapeutic drugs and their side effects.

Among the most common side effects of chemotherapeutic drugs is its nonselective toxicity, where it destroys the normal body cells such as those in the hair follicle,

**157**

**Table 2.**

*with them [26, 28–30].*

*Herbal Remedies for Breast Cancer Prevention and Treatment*

bone marrow, and cells of other important organs along with the cancer cells. Quite a few chemotherapeutic drugs affect the nerve endings or synaptic gaps in hands and feet that may result into numbness, pain, burning or tingling, sensitivity to cold or heat, or weakness in your extremities [31]. Besides, chemotherapeutic drugs may severely damage the immune cells as wells as the brain cells, making the patient vulnerable to infectious diseases and impaired cognitive functions [32]. These side effects may be temporary and may disappear after a few months of completion of chemotherapy. Other critical side effects that arise due to certain chemotherapeutic drugs may last longer—infertility is one of them [33]. Chemotherapeutics that damage ovaries may lead to menopause symptoms, like hot flashes and vaginal dryness, where menstrual cycle becomes irregular or permanently ceases making pregnancy impossible [34]. Further, early menopause in premenopausal women due to the use of aromatase inhibitor agents in adjuvant therapy causes a hypoestrogenic condition that negatively impacts bone density resulting in osteopenia or osteoporosis [35]. Besides, long-term chemotherapeutic toxicity results in cardiac diseases and may trigger secondary cancer such as marrow neoplasm or leukemia [36, 37]. Chemotherapy-linked cardiotoxicity is another major setback of cancer therapy that increases the mortality rate because of the high prevalence of cardiovascular diseases in cancer patients [38]. The cardiotoxicity leads to congestive heart failure (CHF), which is more prevalence in young and elderly patients. It has been reported

*Frequently used chemotherapeutic drugs in breast cancer treatment and their common side effects associated* 

*DOI: http://dx.doi.org/10.5772/intechopen.89669*


#### **Table 2.**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

microtubule stability, hence blocking the transition from metaphase to anaphase [25]. Subsequently, the cell undergoes mitotic arrest or programmed cell death (apoptosis). For instance, vincristine and vinorelbine inhibit the polymerization of microtubules by binding to either the vinca domain or taxoid-binding domain that interferes between β- and α-subunit of tubulin [25]. On the other hand, microtubulestabilizing drugs like paclitaxel hyperstabilizes the microtubule assembly by binding to the inner surface of the microtubule at a taxoid-binding site on β-tubulin resulting in mitotic arrest in the cell [25]. All these strategies helped in reducing mortality due to breast cancer and increased the survival rate; however, they appear with certain side effects that may be either low and short term or high and life threatening.

*Commonly used breast cancer chemotherapeutic drugs, their targets, and mechanism of action [26].*

**4. Chemotherapeutic-associated toxicity in breast cancer treatment**

The role of chemotherapy in curing cancer is still doubtful [27]. Even it decreases the risk of recurrence and helps the patient to live longer with improved quality of life in case of metastatic breast cancer. But its use associated with certain risk factors or side effects—some of the side effects are short term and minor, whereas others may become more serious and life threatening [27]. **Table 2** describes a few commonly used chemotherapeutic drugs and their side effects.

Among the most common side effects of chemotherapeutic drugs is its nonselective toxicity, where it destroys the normal body cells such as those in the hair follicle,

**156**

**Table 1.**

*Frequently used chemotherapeutic drugs in breast cancer treatment and their common side effects associated with them [26, 28–30].*

bone marrow, and cells of other important organs along with the cancer cells. Quite a few chemotherapeutic drugs affect the nerve endings or synaptic gaps in hands and feet that may result into numbness, pain, burning or tingling, sensitivity to cold or heat, or weakness in your extremities [31]. Besides, chemotherapeutic drugs may severely damage the immune cells as wells as the brain cells, making the patient vulnerable to infectious diseases and impaired cognitive functions [32]. These side effects may be temporary and may disappear after a few months of completion of chemotherapy. Other critical side effects that arise due to certain chemotherapeutic drugs may last longer—infertility is one of them [33]. Chemotherapeutics that damage ovaries may lead to menopause symptoms, like hot flashes and vaginal dryness, where menstrual cycle becomes irregular or permanently ceases making pregnancy impossible [34]. Further, early menopause in premenopausal women due to the use of aromatase inhibitor agents in adjuvant therapy causes a hypoestrogenic condition that negatively impacts bone density resulting in osteopenia or osteoporosis [35].

Besides, long-term chemotherapeutic toxicity results in cardiac diseases and may trigger secondary cancer such as marrow neoplasm or leukemia [36, 37]. Chemotherapy-linked cardiotoxicity is another major setback of cancer therapy that increases the mortality rate because of the high prevalence of cardiovascular diseases in cancer patients [38]. The cardiotoxicity leads to congestive heart failure (CHF), which is more prevalence in young and elderly patients. It has been reported that the breast cancer patients aged between 65 and 70 years, who received adjuvant anthracycline chemotherapy, had significantly higher rates of CHF [39]. In another investigation, a widely used chemotherapeutic drug, doxorubicin, was reported to cause CHF in worryingly 26% of the patients suffering from breast carcinoma [40, 41]. Additionally, it was observed that 0.5% of breast cancer patients developed different types of marrow neoplasm (MN) or leukemia after a few years of chemotherapy [42]. The risk of developing MN is higher in the first few years after chemotherapy. Furthermore, chemotherapeutic drugs may also disrupt the normal psychological state of patients in certain cases [43, 44].

The side effects that arise due the conventional chemotherapy is mainly due to lack of specificity of the drugs for cancer cells. Majority of the widely used chemotherapeutic drugs causes adverse damage to normal cells and key organs, which limits the dose of a drug that can be used [45]. This explains the reason why cancer drugs have a low therapeutic index. Several approaches are being considered to address this issue in order to improve the effectiveness of anticancer drugs. One of the popular approaches among them is searching for natural compounds that inhibit cancer cell growth without disrupting the functioning of healthy cells.

### **5. Ethnomedicine and herbal compounds used for cancer treatment**

Plants have played a key role in the survival and evolution of human beings as they have provided the basic need of mankind like food, clothing, shelter, and medicine since the beginning of the human race. Plants have formed the basis of traditional medicine systems like Ayurveda, Unani, and Chinese traditional medicines that have served mankind with their health needs. A larger part of the population in developing and underdeveloped countries relies on herbal medicine for solving treating their primary health issues. Traditional herbal medicines become popular because of their cost-effectiveness, abundancy, and less or no side effects. In recent years, global emphasis on plant research has increased to find out drug-like substances from traditionally used medicinal plants. Moreover, several naturally occurring plant-based compounds like curcumin, resveratrol, quercetin, and many more showed promising anticancerous effects and are gaining interest as an adjuvant chemotherapeutic agent. Besides, naturally occurring compounds cause less toxicity to healthy cells and in certain cases show selective toxicity against abnormal or diseased cells [46]. This might be the reason that today a large number of drugs being marketed are structurally similar to the structure of naturally occurring compounds.

Herbal compounds show a variety of anticancer activity mainly antioxidant, anti-inflammatory, antimutagenic, and apoptosis-inducing activity that may help prevent cancer development in the early stage (**Figure 1**). Dietary consumption of adequate quantity of these herbal products may help in prevention and treatment of breast cancer by cell cycle arrest, induction of apoptosis, regulating carcinogen metabolism and oncogenic expression, inhibiting cell adhesion, proliferation and migration, and blocking signaling pathways that are essential for cancer progression [47].

Between the year 1981 and 2014, 136 anticancer drugs were brought to use around the globe, almost 83% of which were either herbal compounds or their derivatives [48]. A number of anticancer drugs have already in use for the treatment of breast cancer—including vincristine, vinblastine, paclitaxel, and docetaxel [49]. Despite the success of herbal products in curing breast cancer and its associated complexities, not many herbal products are making through preclinical or clinical

**159**

**Figure 2.**

*Some important members of different classes of phytoestrogens [61].*

*Herbal Remedies for Breast Cancer Prevention and Treatment*

trials. Hence, greater effort is necessary to successfully transfer these agents to an

ideal clinical setting to assess their potential for herbal therapies.

*Features of herbal compounds that attribute to their anticancer activity.*

*DOI: http://dx.doi.org/10.5772/intechopen.89669*

**Figure 1.**

*Herbal Remedies for Breast Cancer Prevention and Treatment DOI: http://dx.doi.org/10.5772/intechopen.89669*

**Figure 1.**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

psychological state of patients in certain cases [43, 44].

healthy cells.

ring compounds.

for cancer progression [47].

that the breast cancer patients aged between 65 and 70 years, who received adjuvant anthracycline chemotherapy, had significantly higher rates of CHF [39]. In another investigation, a widely used chemotherapeutic drug, doxorubicin, was reported to cause CHF in worryingly 26% of the patients suffering from breast carcinoma [40, 41]. Additionally, it was observed that 0.5% of breast cancer patients developed different types of marrow neoplasm (MN) or leukemia after a few years of chemotherapy [42]. The risk of developing MN is higher in the first few years after chemotherapy. Furthermore, chemotherapeutic drugs may also disrupt the normal

The side effects that arise due the conventional chemotherapy is mainly due to lack of specificity of the drugs for cancer cells. Majority of the widely used chemotherapeutic drugs causes adverse damage to normal cells and key organs, which limits the dose of a drug that can be used [45]. This explains the reason why cancer drugs have a low therapeutic index. Several approaches are being considered to address this issue in order to improve the effectiveness of anticancer drugs. One of the popular approaches among them is searching for natural compounds that inhibit cancer cell growth without disrupting the functioning of

**5. Ethnomedicine and herbal compounds used for cancer treatment**

Plants have played a key role in the survival and evolution of human beings as they have provided the basic need of mankind like food, clothing, shelter, and medicine since the beginning of the human race. Plants have formed the basis of traditional medicine systems like Ayurveda, Unani, and Chinese traditional medicines that have served mankind with their health needs. A larger part of the population in developing and underdeveloped countries relies on herbal medicine for solving treating their primary health issues. Traditional herbal medicines become popular because of their cost-effectiveness, abundancy, and less or no side effects. In recent years, global emphasis on plant research has increased to find out drug-like substances from traditionally used medicinal plants. Moreover, several naturally occurring plant-based compounds like curcumin, resveratrol, quercetin, and many more showed promising anticancerous effects and are gaining interest as an adjuvant chemotherapeutic agent. Besides, naturally occurring compounds cause less toxicity to healthy cells and in certain cases show selective toxicity against abnormal or diseased cells [46]. This might be the reason that today a large number of drugs being marketed are structurally similar to the structure of naturally occur-

Herbal compounds show a variety of anticancer activity mainly antioxidant, anti-inflammatory, antimutagenic, and apoptosis-inducing activity that may help prevent cancer development in the early stage (**Figure 1**). Dietary consumption of adequate quantity of these herbal products may help in prevention and treatment of breast cancer by cell cycle arrest, induction of apoptosis, regulating carcinogen metabolism and oncogenic expression, inhibiting cell adhesion, proliferation and migration, and blocking signaling pathways that are essential

Between the year 1981 and 2014, 136 anticancer drugs were brought to use around the globe, almost 83% of which were either herbal compounds or their derivatives [48]. A number of anticancer drugs have already in use for the treatment of breast cancer—including vincristine, vinblastine, paclitaxel, and docetaxel [49]. Despite the success of herbal products in curing breast cancer and its associated complexities, not many herbal products are making through preclinical or clinical

**158**

*Features of herbal compounds that attribute to their anticancer activity.*

trials. Hence, greater effort is necessary to successfully transfer these agents to an ideal clinical setting to assess their potential for herbal therapies.

**Figure 2.** *Some important members of different classes of phytoestrogens [61].*

### **6. Herbal products used for prevention of breast cancer**

Breast cancer is a preventable disease [50]. Estrogens play a major role in promoting the proliferation of normal breast cells as well as neoplastic breast epithelium [51]. Almost 40–70% of breast cancers are estrogen receptor positive [52]. Hence, blocking the estrogen receptor for the treatment and chemoprevention of breast cancer is one of the significant approaches. Plant-based estrogen-like compounds or phytoestrogens were originally proposed as cancer-protective agents. This claim was strongly supported by an epidemiological study that revealed a low breast cancer incidence in the soy-consuming population [53, 54]. Phytoestrogens are structural analogues of the mammalian hormone, estrogen, and thus can bind weakly to the hormone receptor [55]. Structurally, phytoestrogen can be grouped into flavones, flavanones, lignans, coumestans, and stilbenes [56]. The structure of important members of different classes of phytoestrogens is given in **Figure 2**. Soybean and soy product is a rich source of isoflavones [57]. Other phytoestrogen classes are legumes and lignans found in seeds, nuts, whole grains, fruit, and vegetables [57]. Historically, the rate of breast cancer occurrence in the United States is 4–7 times higher than that of Asian population where the consumption of dietary isoflavones is comparatively as higher as 20 to 80 mg/d [58]. In addition, epidemiological observations also revealed a modest 30% reduction in breast cancer risk for women with a higher percentage of dietary lignan intake [57]. Therefore, consumption of phytoestrogen-rich diet is one of the many potential protective lifestyles against breast cancer. Recently, there are increasing pieces of evidence that phytoestrogen activity inhibits key steroidogenic enzymes activity involved in the synthesis of estradiol from circulating androgens and estrogen sulfate [7]. Consequently, this activity could play a major role in protection against breast cancer. Besides inhibiting the estrogenic activity, phytoestrogens were also reported to activate the G-protein coupled receptor, GPR30 or GPER-1, described as a novel estrogen receptor and play a significant role in estrogen-dependent diseases like breast cancer [59]. However, the activity of phytoestrogens is unclear and depends on more than one factors that include—its structure, metabolism, its relative availability compared to that of endogenous estrogen [60, 57].

Naturally occurring phenolic compounds namely phenolic acids, flavonoids, tannins, quinones, anthocyanins, and others play an important role in cancer prevention and/or treatment [47]. These phenolic compounds are ubiquitous and rich in medicinal herbs and dietary plants. Several phenolic compounds contribute toward inhibiting carcinogenesis mechanism and show chemopreventive activities by their diverse range of biological activities [62] (**Table 4**).

#### **7. Herbal products used for treatment of breast cancer**

A recent population-based survey showed that almost 80% of the women suffering from breast cancer use some form of complementary or alternative medicine for the treatment of cancer [63]. Herbal remedies are the most common and popular form of alternative medicine among them, which is frequently used by women suffering from breast cancer. Here is some evidence that can help to treat breast cancer and its associated toxicity:

#### **7.1 Choosing a selectively cytotoxic herbal cure**

One of the interesting features for herbal remedies is their selective toxicity toward cancer cells. There are a number of phytocompounds reported that have

**161**

**Table 3.**

*Herbal Remedies for Breast Cancer Prevention and Treatment*

selective toxicity toward breast cancer cells. Artemisinin is one among them, isolated from *Artemisia annua* L. proved to be selectively cytotoxic toward breast cancer cells when an adequate amount of iron (i.e., ferrous iron) is present in the cells. Because cancer cells have a higher iron influx, therefore, artemisinin and its analogues can selectively destroy cancer cells under high iron concentration [64]. Besides, polyphenols from *Artemisia annua* L. were reported to inhibit the adhesion and epithelial-mesenchymal transition (EMT) of highly metastatic breast cancer cells, MDA-MB-231 [65]. Other than this, polyphenol-rich extracts of *Hibiscus sabdariffa* and aqueous extract of *Brucea javanica* were also reported to show selective cytotoxicity toward *MCF7* and HTB-126 breast cancer cell lines, respectively [66, 67]. However, further exploration is necessary to isolate the selective cytotoxic

*Plant-based cancer therapeutics in different stages of clinical trials and research [68].*

**7.2 Combination therapy by herbal remedies and synthetic drugs**

Combination therapy of herbal therapy and synthetic drugs possibly be the last resource for patients in the final stage of breast cancer, where surgery is not possible [69]. The combinatory effect of a herbal drug with conventional cancer drugs might improve the bioavailability of one of them making the treatment more effective [69, 70]. Additionally, the combinatory use of herbal remedies with chemotherapy will reduce the dose of standard medicine resulting in lower toxicity and side effects [71]. Several researchers have suggested that herbal compounds can be used in a therapeutic modality as it enhances the anticancer activity of current drugs. Curcumin, a renowned anticancer herbal compound down-regulated the expression of breast cancer markers *in vivo* and *in vitro* when administered along with

*DOI: http://dx.doi.org/10.5772/intechopen.89669*

ingredients of these plants (**Table 3**).

#### *Herbal Remedies for Breast Cancer Prevention and Treatment DOI: http://dx.doi.org/10.5772/intechopen.89669*


#### **Table 3.**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

compared to that of endogenous estrogen [60, 57].

**7.1 Choosing a selectively cytotoxic herbal cure**

by their diverse range of biological activities [62] (**Table 4**).

**7. Herbal products used for treatment of breast cancer**

**6. Herbal products used for prevention of breast cancer**

Breast cancer is a preventable disease [50]. Estrogens play a major role in promoting the proliferation of normal breast cells as well as neoplastic breast epithelium [51]. Almost 40–70% of breast cancers are estrogen receptor positive [52]. Hence, blocking the estrogen receptor for the treatment and chemoprevention of breast cancer is one of the significant approaches. Plant-based estrogen-like compounds or phytoestrogens were originally proposed as cancer-protective agents. This claim was strongly supported by an epidemiological study that revealed a low breast cancer incidence in the soy-consuming population [53, 54]. Phytoestrogens are structural analogues of the mammalian hormone, estrogen, and thus can bind weakly to the hormone receptor [55]. Structurally, phytoestrogen can be grouped into flavones, flavanones, lignans, coumestans, and stilbenes [56]. The structure of important members of different classes of phytoestrogens is given in **Figure 2**. Soybean and soy product is a rich source of isoflavones [57]. Other phytoestrogen classes are legumes and lignans found in seeds, nuts, whole grains, fruit, and vegetables [57]. Historically, the rate of breast cancer occurrence in the United States is 4–7 times higher than that of Asian population where the consumption of dietary isoflavones is comparatively as higher as 20 to 80 mg/d [58]. In addition, epidemiological observations also revealed a modest 30% reduction in breast cancer risk for women with a higher percentage of dietary lignan intake [57]. Therefore, consumption of phytoestrogen-rich diet is one of the many potential protective lifestyles against breast cancer. Recently, there are increasing pieces of evidence that phytoestrogen activity inhibits key steroidogenic enzymes activity involved in the synthesis of estradiol from circulating androgens and estrogen sulfate [7]. Consequently, this activity could play a major role in protection against breast cancer. Besides inhibiting the estrogenic activity, phytoestrogens were also reported to activate the G-protein coupled receptor, GPR30 or GPER-1, described as a novel estrogen receptor and play a significant role in estrogen-dependent diseases like breast cancer [59]. However, the activity of phytoestrogens is unclear and depends on more than one factors that include—its structure, metabolism, its relative availability

Naturally occurring phenolic compounds namely phenolic acids, flavonoids, tannins, quinones, anthocyanins, and others play an important role in cancer prevention and/or treatment [47]. These phenolic compounds are ubiquitous and rich in medicinal herbs and dietary plants. Several phenolic compounds contribute toward inhibiting carcinogenesis mechanism and show chemopreventive activities

A recent population-based survey showed that almost 80% of the women suffering from breast cancer use some form of complementary or alternative medicine for the treatment of cancer [63]. Herbal remedies are the most common and popular form of alternative medicine among them, which is frequently used by women suffering from breast cancer. Here is some evidence that can help to treat breast cancer

One of the interesting features for herbal remedies is their selective toxicity toward cancer cells. There are a number of phytocompounds reported that have

**160**

and its associated toxicity:

*Plant-based cancer therapeutics in different stages of clinical trials and research [68].*

selective toxicity toward breast cancer cells. Artemisinin is one among them, isolated from *Artemisia annua* L. proved to be selectively cytotoxic toward breast cancer cells when an adequate amount of iron (i.e., ferrous iron) is present in the cells. Because cancer cells have a higher iron influx, therefore, artemisinin and its analogues can selectively destroy cancer cells under high iron concentration [64]. Besides, polyphenols from *Artemisia annua* L. were reported to inhibit the adhesion and epithelial-mesenchymal transition (EMT) of highly metastatic breast cancer cells, MDA-MB-231 [65]. Other than this, polyphenol-rich extracts of *Hibiscus sabdariffa* and aqueous extract of *Brucea javanica* were also reported to show selective cytotoxicity toward *MCF7* and HTB-126 breast cancer cell lines, respectively [66, 67]. However, further exploration is necessary to isolate the selective cytotoxic ingredients of these plants (**Table 3**).

### **7.2 Combination therapy by herbal remedies and synthetic drugs**

Combination therapy of herbal therapy and synthetic drugs possibly be the last resource for patients in the final stage of breast cancer, where surgery is not possible [69]. The combinatory effect of a herbal drug with conventional cancer drugs might improve the bioavailability of one of them making the treatment more effective [69, 70]. Additionally, the combinatory use of herbal remedies with chemotherapy will reduce the dose of standard medicine resulting in lower toxicity and side effects [71]. Several researchers have suggested that herbal compounds can be used in a therapeutic modality as it enhances the anticancer activity of current drugs. Curcumin, a renowned anticancer herbal compound down-regulated the expression of breast cancer markers *in vivo* and *in vitro* when administered along with

chemotherapeutic drugs cyclophosphamide and paclitaxel that made the cancer cells more viable to the drugs [72, 73]. Similarly, 20S-protopanaxadiol, a metabolite of ginsenosides, inhibited cell proliferation in MCF-7 cells by interfering with estrogenic gene expression when used in combination with tamoxifen [74]. Besides, this combination asynergistically improved the cytotoxicity of tamoxifen in an ER-independent manner [74]. Hence, the benefits of these herbal compounds in synergistic therapy are considerable, and this might help to overcome chemotherapeutic drug resistance and toxicity in breast cancer treatment.

### **7.3 Herbal supplements and nutraceuticals for breast cancer therapy**

Cancer has been shown to be a preventable disease with changes in nutrition and dietary changes. A previous investigation showed that almost 35% of cancers are related to diet [75]. There are several confirmations from epidemiological and laboratory studies that sufficient intake of fruit, vegetables, and herbal supplements is inversely linked with breast cancer occurrence. A diet composed of adequate quantity of phytoestrogens, polyphenols, and rich sources of other chemopreventive agents helps in reducing breast cancer risk. Dietary supplements of the herbal source are less toxic and easily metabolized. Besides, dietary consumption of these herbal remedies helps in fighting side effects in postchemotherapy patients. One of the primary symptoms of adjuvant chemotherapeutic damage in posttherapy breast cancer patients is hot flushes. Black cohosh or *Actaea racemosa* plant is popularly used by patients of breast cancer to treat hot flushes, which gives conflicting but promising results [76].

### **8. Molecular mechanism of anticancerous activity of herbal compounds on breast cancer**

As discussed in the earlier section, herbal compounds show a verity of anticancer actions—including antioxidant, cytotoxic, antiproliferative, apoptotic activity, etc. Plant-based cancer agents broadly classified into five groups that include—methyltranferase inhibitors, DNA protecting agents, antioxidants, histone deacetylases inhibitors, and mitosis disruptors. Generally, plant-derived compounds contribute toward the anticarcinogenesis mechanism by their antioxidant, cytotoxic, antimitotic, and apoptotic activity (**Table 4**). Others help in chemoprevention by preventing DNA damage, modulating carcinogenesis signaling, and inducing apoptotic cell death (**Table 4**). Several *in vitro* and *in vivo* investigations support the activity of herbal compounds that linked with their anticancer activity. Here's is a few examples of the anticancer mechanism of herbal compounds.

#### **8.1 Antioxidant activity of herbal compounds**

Antioxidant activity of herbal compounds of oxidative stress is developed when the balance between the production of reactive oxygen species (free radicals) and antioxidant defense is disturbed [77]. Oxidative stress development and consequent reactive oxygen species (ROS) generation are linked with several disease pathogenesis including cancer. Oxidative stress is dealt with by the body's antioxidant mechanism and several herbal compounds help boosting this machinery. For instance, curcumin enhances the activity of antioxidant enzymes resulting in enhanced cellular resistance to oxidative damage [78]. In addition, curcumin was also found to rise hepatic GSH, SOD, GPx, GR, GST, and CAT activities in paracetamol-treated rats [79]. Other plant-based compounds like epigallocatechin gallate, a component

**163**

Delphinidin 3-sambubioside

Epicatechin gallate

*Herbal Remedies for Breast Cancer Prevention and Treatment*

Biochanin A *Trifolium* 

Genistein Component of

Artemisinin *Artemisia annua* Selective

Bacosine *Bacopa monnieri* Anti-metastatic

Curcumin *Curcuma longa* Chemopreventive

**Compound Structure Herbal source Activity References**

*Brassica nigra, Brassica juncea*

*pratense*

*Hibiscus sabdariffa*

*Parapiptadenia rigida, Hibiscus sabdariffa,* component of green tea

soy products

Chemoprevention, detoxification, and reduces cancer risks. Inhibits mitosis and angiogenesis. Shows selective cytotoxicity.

cytotoxicity, mitotic arrest, apoptosis, inhibition of angiogenesis, and ferroptosis.

Breast cancer preventive agent inhibits tumor growth.

activity.

and antitumoral activities, anti-metastatic, apoptotic, modulate carcinogenesis signaling, help reducing drug toxicity.

Antioxidant, cytotoxic, apoptotic, induces autophagy and necrosis.

Induces apoptosis and inhibits tumorigenesis, potential cancer chemopreventive

Chemoprevention, estrogenic activity, inhibition of tumorigenesis, inhibit topoisomerase II activity and angiogenesis

agent.

[86, 87]

[88, 89]

[90, 91]

[92, 93]

[94–96]

[97, 98]

[99–101]

[102–104]

*DOI: http://dx.doi.org/10.5772/intechopen.89669*

Allyl isothiocyanate *Herbal Remedies for Breast Cancer Prevention and Treatment DOI: http://dx.doi.org/10.5772/intechopen.89669*

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

peutic drug resistance and toxicity in breast cancer treatment.

**7.3 Herbal supplements and nutraceuticals for breast cancer therapy**

Cancer has been shown to be a preventable disease with changes in nutrition and dietary changes. A previous investigation showed that almost 35% of cancers are related to diet [75]. There are several confirmations from epidemiological and laboratory studies that sufficient intake of fruit, vegetables, and herbal supplements is inversely linked with breast cancer occurrence. A diet composed of adequate quantity of phytoestrogens, polyphenols, and rich sources of other chemopreventive agents helps in reducing breast cancer risk. Dietary supplements of the herbal source are less toxic and easily metabolized. Besides, dietary consumption of these herbal remedies helps in fighting side effects in postchemotherapy patients. One of the primary symptoms of adjuvant chemotherapeutic damage in posttherapy breast cancer patients is hot flushes. Black cohosh or *Actaea racemosa* plant is popularly used by patients of breast cancer to treat hot flushes, which gives conflicting but promising results [76].

**8. Molecular mechanism of anticancerous activity of herbal compounds** 

As discussed in the earlier section, herbal compounds show a verity of anticancer actions—including antioxidant, cytotoxic, antiproliferative, apoptotic activity, etc. Plant-based cancer agents broadly classified into five groups that include—methyltranferase inhibitors, DNA protecting agents, antioxidants, histone deacetylases inhibitors, and mitosis disruptors. Generally, plant-derived compounds contribute toward the anticarcinogenesis mechanism by their antioxidant, cytotoxic, antimitotic, and apoptotic activity (**Table 4**). Others help in chemoprevention by preventing DNA damage, modulating carcinogenesis signaling, and inducing apoptotic cell death (**Table 4**). Several *in vitro* and *in vivo* investigations support the activity of herbal compounds that linked with their anticancer activity.

Here's is a few examples of the anticancer mechanism of herbal compounds.

Antioxidant activity of herbal compounds of oxidative stress is developed when the balance between the production of reactive oxygen species (free radicals) and antioxidant defense is disturbed [77]. Oxidative stress development and consequent reactive oxygen species (ROS) generation are linked with several disease pathogenesis including cancer. Oxidative stress is dealt with by the body's antioxidant mechanism and several herbal compounds help boosting this machinery. For instance, curcumin enhances the activity of antioxidant enzymes resulting in enhanced cellular resistance to oxidative damage [78]. In addition, curcumin was also found to rise hepatic GSH, SOD, GPx, GR, GST, and CAT activities in paracetamol-treated rats [79]. Other plant-based compounds like epigallocatechin gallate, a component

**8.1 Antioxidant activity of herbal compounds**

chemotherapeutic drugs cyclophosphamide and paclitaxel that made the cancer cells more viable to the drugs [72, 73]. Similarly, 20S-protopanaxadiol, a metabolite of ginsenosides, inhibited cell proliferation in MCF-7 cells by interfering with estrogenic gene expression when used in combination with tamoxifen [74]. Besides, this combination asynergistically improved the cytotoxicity of tamoxifen in an ER-independent manner [74]. Hence, the benefits of these herbal compounds in synergistic therapy are considerable, and this might help to overcome chemothera-

**162**

**on breast cancer**



#### **Table 4.**

*Some novel compounds from herbal sources that showed promising anticancerous activity in both* in vivo *and*  in vitro *studies.*

of in green tea, found to reduce the levels of lipid peroxidation and protein carbonyl content in rats, possibly by enhancing the GSH redox status significantly when administered orally [80]. Likewise, several herbal compounds help to reduce oxidative stress, hence play a preventive role against cancer onset.

#### **8.2 Anti-angiogenesis activity of herbal compounds**

Quite a few herbal compounds help to inhibit angiogenesis in breast cancer. Genistein, a flavonoid phytoestrogen, is the most potent angiogenesis inhibitor linked with reduced expression of VEGF, PDGF, uPA, and MMP-2 and MMP-9 [81]. Curcumin was even found to be an effective inhibitor of angiogenesis that reduces the expression of various proangiogenic proteins such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor [82]. Resveratrol and quercetin inhibited the migration and tube formation in bovine aorta endothelial cells consequently inhibiting angiogenesis in those cells [83, 84]. In addition, catechin derivatives, such as epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (EGCG), present in green tea are potent angiogenesis inhibitors [85]. The anti-angiogenic activity of EGCG was demonstrated by inhibition of vascular endothelial growth factor (VEGF) production and reduction of matrix metalloproteinase-2 (MMP-2) activity in MDA-MB231 breast cancer cells [85].

**165**

**9. Conclusion**

*Herbal Remedies for Breast Cancer Prevention and Treatment*

**8.3 Apoptosis-inducing activity of herbal compounds**

T-47D along with endometrial (ECC-1) cancer cells [108].

The apoptosis-inducing activity of herbal compounds is another favorable feature that contributes toward their anticancer effect. Curcumin was found to inhibit the proliferation and inducing apoptosis in several cancer cell lines including breast cancer cells such as T47D, MCF7, MDA-MB-231, and MDA-MB-468 [115]. Curcumin inhibited the phosphorylation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR), decreased BCL2 expression, and elevated BAX expression and cleavage of caspase 3, subsequently inducing apoptosis of breast cancer cells [115]. Protocatechuic acid was also found to be a potent apoptosis inducer in five types of human cancer cell lines including breast, lung, liver, cervix, and prostate cancer cells [111], which was confirmed by DNA fragmentation, changes in mitochondrial membrane potential, and measurement of caspase activity. The flavonoid 8-prenylnaringenin (8PN), a constituent of *Humulus lupulus*, is an effective phytocompound known for its growth-inhibiting and apoptotic activity in various human cancer types including breast cancer [116]. This activity of 8PN in MCF7 breast cancer cells was possibly mediated by interference with an ER-associated PI3K pathway [116]. Other herbal compounds like lycopene inhibit cell cycle progression by reducing cyclin D expression and retention of p27 in cyclin E–cdk2, thus leading to inhibition of G1 CDK activities in human breast cell line MCF-7 and

Interestingly, artemisinin, which is an ancient Chinese herbal compound for malarial fevers, has been recently found to have potent and selective toxicity against cancer cells. It reacts with iron to form free radicals with alkylating capacity that can kill cells. As cancer cells require a large quantity of iron uptake to proliferate, making them more susceptible to the cytotoxic effect of artemisinin [117]. Besides, oral administration of artemisinin delayed the onset of breast cancer in 7, 12-dimethylbenz [a] anthracene (DMBA)-induced rats [118]. This encouraging results might lead to design novel chemotherapeutics with effective anticancer property and low toxicity.

Though, advances in healthcare research lead to the identification and characterization of most breast cancer types and corresponding cure. However, incidence and prevalence of breast cancer is rising in terrifying rate in both developed and developing countries because of various risk factors. Improved synthetic drugs and hormonal therapy emerged in a decline in breast cancer incidences, increased survival, and better life quality. However, prolonged use of synthetic anticancer drugs is linked with several health risks or side effects that consequence from the toxic effect of these drugs in normal cells. Chemoprevention by herbal compounds is of great interest and is considered to be an inexpensive, readily applicable, acceptable, and accessible approach to cancer control and management. Herbal remedies play a significant role in the management of breast cancer and the associated therapeutic toxicity. The adjunct use of herbal products and chemotherapy can be an efficient and cost-effective way to treat breast cancer. Such adjuvant therapy proved to produce a synergistic anticancer effect that reduced the drug toxicity, suppresses drug resistance, and provides quick drug action enhancing the quality of treatment. Besides, combinatory therapy might also increase the therapeutic index of the synthetic partner by improving the efficiency of the drug. Plant-derived anticancer drugs such as vinblastine, vincristine, taxols, etc. showed encouraging chemotherapeutic potential that is currently used in breast cancer treatment and a large number of them are in preclinical or in clinical trials. In the last decade, a vast number of phytochemicals were identified that showed encouraging anticancer

*DOI: http://dx.doi.org/10.5772/intechopen.89669*

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

Lycopene Component

Ursolic acid Many plants

Glycyrrhetinic

Protocatechuic

acid

**Table 4.**

in vitro *studies.*

acid

**Compound Structure Herbal source Activity References**

*Glycyrrhiza glabra*

of tomatoes, pink grapefruit, apricots, red oranges.

Dietary polyphenol found in many foods including *Hibiscus sabdariffa, Ginkgo biloba, Hypericum perforatum*

including *Malus domestica*, *Origanum majorana*

Inhibition of cell proliferation, synergistic effect in combination with an anticancer drug, etoposide. Antineoplastic effect including apoptosis.

Inhibition of cell cycle progression

Apoptosisinducing agent, anti-metastatic.

Antitumor, antioxidant, antiinflammatory, and anti-angiogenesis activity.

[105, 106]

[107, 108]

[109–111]

[112–114]

of in green tea, found to reduce the levels of lipid peroxidation and protein carbonyl content in rats, possibly by enhancing the GSH redox status significantly when administered orally [80]. Likewise, several herbal compounds help to reduce oxida-

*Some novel compounds from herbal sources that showed promising anticancerous activity in both* in vivo *and* 

Quite a few herbal compounds help to inhibit angiogenesis in breast cancer. Genistein, a flavonoid phytoestrogen, is the most potent angiogenesis inhibitor linked with reduced expression of VEGF, PDGF, uPA, and MMP-2 and MMP-9 [81]. Curcumin was even found to be an effective inhibitor of angiogenesis that reduces the expression of various proangiogenic proteins such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor [82]. Resveratrol and quercetin inhibited the migration and tube formation in bovine aorta endothelial cells consequently inhibiting angiogenesis in those cells [83, 84]. In addition, catechin derivatives, such as epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (EGCG), present in green tea are potent angiogenesis inhibitors [85]. The anti-angiogenic activity of EGCG was demonstrated by inhibition of vascular endothelial growth factor (VEGF) production and reduction of matrix metalloproteinase-2 (MMP-2) activity in MDA-MB231 breast cancer cells [85].

tive stress, hence play a preventive role against cancer onset.

**8.2 Anti-angiogenesis activity of herbal compounds**

**164**

### **8.3 Apoptosis-inducing activity of herbal compounds**

The apoptosis-inducing activity of herbal compounds is another favorable feature that contributes toward their anticancer effect. Curcumin was found to inhibit the proliferation and inducing apoptosis in several cancer cell lines including breast cancer cells such as T47D, MCF7, MDA-MB-231, and MDA-MB-468 [115]. Curcumin inhibited the phosphorylation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR), decreased BCL2 expression, and elevated BAX expression and cleavage of caspase 3, subsequently inducing apoptosis of breast cancer cells [115]. Protocatechuic acid was also found to be a potent apoptosis inducer in five types of human cancer cell lines including breast, lung, liver, cervix, and prostate cancer cells [111], which was confirmed by DNA fragmentation, changes in mitochondrial membrane potential, and measurement of caspase activity. The flavonoid 8-prenylnaringenin (8PN), a constituent of *Humulus lupulus*, is an effective phytocompound known for its growth-inhibiting and apoptotic activity in various human cancer types including breast cancer [116]. This activity of 8PN in MCF7 breast cancer cells was possibly mediated by interference with an ER-associated PI3K pathway [116]. Other herbal compounds like lycopene inhibit cell cycle progression by reducing cyclin D expression and retention of p27 in cyclin E–cdk2, thus leading to inhibition of G1 CDK activities in human breast cell line MCF-7 and T-47D along with endometrial (ECC-1) cancer cells [108].

Interestingly, artemisinin, which is an ancient Chinese herbal compound for malarial fevers, has been recently found to have potent and selective toxicity against cancer cells. It reacts with iron to form free radicals with alkylating capacity that can kill cells. As cancer cells require a large quantity of iron uptake to proliferate, making them more susceptible to the cytotoxic effect of artemisinin [117]. Besides, oral administration of artemisinin delayed the onset of breast cancer in 7, 12-dimethylbenz [a] anthracene (DMBA)-induced rats [118]. This encouraging results might lead to design novel chemotherapeutics with effective anticancer property and low toxicity.

#### **9. Conclusion**

Though, advances in healthcare research lead to the identification and characterization of most breast cancer types and corresponding cure. However, incidence and prevalence of breast cancer is rising in terrifying rate in both developed and developing countries because of various risk factors. Improved synthetic drugs and hormonal therapy emerged in a decline in breast cancer incidences, increased survival, and better life quality. However, prolonged use of synthetic anticancer drugs is linked with several health risks or side effects that consequence from the toxic effect of these drugs in normal cells. Chemoprevention by herbal compounds is of great interest and is considered to be an inexpensive, readily applicable, acceptable, and accessible approach to cancer control and management. Herbal remedies play a significant role in the management of breast cancer and the associated therapeutic toxicity. The adjunct use of herbal products and chemotherapy can be an efficient and cost-effective way to treat breast cancer. Such adjuvant therapy proved to produce a synergistic anticancer effect that reduced the drug toxicity, suppresses drug resistance, and provides quick drug action enhancing the quality of treatment. Besides, combinatory therapy might also increase the therapeutic index of the synthetic partner by improving the efficiency of the drug. Plant-derived anticancer drugs such as vinblastine, vincristine, taxols, etc. showed encouraging chemotherapeutic potential that is currently used in breast cancer treatment and a large number of them are in preclinical or in clinical trials. In the last decade, a vast number of phytochemicals were identified that showed encouraging anticancer

activity *in vivo* and *in vitro* breast cancer models. Interestingly, several compounds like artemisinin and isothiocyanates showed selective toxicity toward cancer cells, which recommend clinical trials of these compounds. Furthermore, phytoestrogens with affinity and capacity to produce functional responses through estrogen receptors revealed unique possibilities of using them in hormone replacement therapy. Overall, this chapter can conclude that understanding the molecular mechanism of interaction between herbal compounds and cancer cells in the tumoral environment can help us to design novel anticancer drugs that are less toxic and affordable. This reflects the fact that these goals will only be attainable if the herbal compounds that showed promising anticancer activity can be successfully transferred to an ideal clinical setting for the use of herbal therapies.

### **Author details**

Yahyea Baktiar Laskar, Romen Meitei Lourembam and Pranab Behari Mazumder\* Natural Product and Biomedicine Research Laboratory, Department of Biotechnology, Assam University, Cachar, Assam, India

\*Address all correspondence to: pbmazumder65@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**167**

*Herbal Remedies for Breast Cancer Prevention and Treatment*

[10] Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary hormonal contraception and the risk of breast cancer. The New England Journal of Medicine. 2017;**377**(23):2228-2239

[11] Hanahan D, Weinberg RA. Hallmarks of cancer: The next

2007;**117**(5):1175-1183

2010;**7**:251-265

2016;**8**(9)

generation. Cell. 2011;**144**(5):646-674

[12] Lin W, Karin M, Lin W, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer find the latest version: Review series a cytokine-mediated link between innate immunity, inflammation, and cancer. The Journal of Clinical Investigation.

[13] Harris TJR, McCormick F. The molecular pathology of cancer. Nature Reviews. Clinical Oncology.

[14] Wickenden JA, Watson CJ. Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: A play in 3 Akts. Breast Cancer Research. 2010;**12**(2):202

[15] Dayem AA, Choi HY, Yang GM, Kim K, Saha SK, Cho SG. The anticancer effect of polyphenols against breast cancer and cancer stem cells: Molecular mechanisms. Nutrients.

[16] Fresco P, Borges F, Diniz C, Marques MPM. New insights on the anticancer properties of dietary polyphenols. Medicinal Research

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of breast cancer. Best Practice &

Reviews. 2006;**26**:747-766

2011;**68**(2):121-128

*DOI: http://dx.doi.org/10.5772/intechopen.89669*

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Yahyea Baktiar Laskar, Romen Meitei Lourembam and Pranab Behari Mazumder\*

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Natural Product and Biomedicine Research Laboratory, Department of

Biotechnology, Assam University, Cachar, Assam, India

provided the original work is properly cited.

\*Address all correspondence to: pbmazumder65@gmail.com

**166**

**Author details**

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[8] Anand P et al. Cancer is a preventable disease that requires major lifestyle changes. Pharmaceutical Research. 2008;**25**(9):2097-2116

[9] Lambertini M et al. Reproductive behaviors and risk of developing breast cancer according to tumor subtype: A systematic review and meta-analysis of epidemiological studies. Cancer Treatment Reviews. 2016;**49**:65-76

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*Medicinal Plants - Use in Prevention and Treatment of Diseases*

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Hai T. Chemotherapy-exacerbated breast cancer metastasis: A paradox

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[29] L SC, Abram R. Side effects of adjuvant treatment of breast cancer. The New England Journal of Medicine.

[30] Partridge AH, Burstein HJ,

and combined chemohormonal therapy in women with early-stage breast cancer. Journal of the National Cancer Institute. Monographs.

Winer EP. Side effects of chemotherapy

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[32] Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nature Reviews. Immunology.

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[34] Blumenfeld Z. Chemotherapy and fertility. Best Practice & Research. Clinical Obstetrics & Gynaecology.

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[108] Nahum A et al. Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27 Kip1 in the cyclin E-cdk2 complexes. Oncogene. 2001;**20**(26):3428-3436

[109] Kakkar S, Bais S. A review on protocatechuic acid and its pharmacological potential. ISRN Pharmacology. 2014;**2014**(4):1-9

[110] Tseng TH et al. Inhibitory effect of hibiscus protocatechuic acid on tumor promotion in mouse skin. Cancer Letters. 1998;**126**(2):199-207

[111] Yin MC, Lin CC, Wu HC, Tsao SM, Hsu CK. Apoptotic effects of protocatechuic acid in human breast, lung, liver, cervix, and prostate cancer cells: Potential mechanisms of action. Journal of Agricultural and Food Chemistry. 2009;**57**(14):6468-6473

[112] Woźniak Ł, Skąpska S, Marszałek K. Ursolic acid - a pentacyclic triterpenoid with a wide spectrum of pharmacological activities. Molecules. 2015;**20**(11):20614-20641

[113] Jäger S, Trojan H, Kopp T, Laszczyk MN, Scheffler A. Pentacyclic triterpene distribution in various plants - rich sources for a new group of multi-potent plant extracts. Molecules. 2009;**14**(6):2016-2031

[114] Mizushina Y, Iida A, Ohta K, Sugawara F, Sakaguchi K. Novel triterpenoids inhibit both DNA polymerase and DNA topoisomerase. The Biochemical Journal. 2000;**350**(3):757-763

[115] Hu S, Xu Y, Meng L, Huang L, Sun H. Curcumin inhibits proliferation and promotes apoptosis of breast cancer cells. Experimental and Therapeutic Medicine. 2018;**16**:1266-1272

[116] Brunelli E, Minassi A, Appendino G, Moro L. 8-Prenylnaringenin, inhibits estrogen receptor-α mediated cell growth and induces

apoptosis in MCF-7 breast cancer cells. The Journal of Steroid Biochemistry and Molecular Biology. 2007;**107**(3-5):140-148

[117] Konstat-Korzenny E, Ascencio-Aragón J, Niezen-Lugo S, Vázquez-López R. Artemisinin and its synthetic derivatives as a possible therapy for cancer. Medical Science. 2018;**6**(1):19

[118] Lai H, Singh NP. Oral artemisinin prevents and delays the development breast cancer in the rat. Cancer Letters. 2006;**231**:43-48

**175**

**Chapter 11**

**Abstract**

intervention.

western world.

*Chi Chiu Wang and Lu Li*

Chinese Herbal Medicine and Its

*Rongyun Wang, Qiuhua Sun, Yifan Lin, Ling Wang, Yuan Liu,* 

Chinese herbal medicines (CHMs) have been widely used to promote health and treat illnesses in daily medical care throughout Asia while mostly accepted as an alternative medical method in many nations of the western world. CHM has a unique therapeutic effect to reduce adverse effects on cancer patients caused by chemotherapy and surgery; however, we did not find any high-quality review for the claimed effects. In this review, we will summarize the history, basic theories and principles, and clinical applications of CHM for disorders, especially female cancers. Meta-analyses to evaluate the efficacy and safety of CHM in the treatment of ovarian cancer and breast cancer have been conducted. The results showed that combined CHMs and western medicines treatment (CHM-WM) had significantly relieved the symptoms and reduced the side effects after surgery and chemotherapy on both ovarian cancer and breast cancer. However, more high-quality and large-scale RCTs are necessary to confirm the efficacy and safety of CHM-WM

**Keywords:** Chinese herbal medicines, female cancer, efficacy and safety,

**1. Traditional Chinese medicine and Chinese herbal medicines**

Traditional Chinese medicine (TCM) has a history that spans 5000 years and has been widely used to promote health and treat illnesses [1]. Although TCM has such wide applications as an important part in daily medical care throughout Asia, it is mostly accepted as an alternative medical method in many nations of the

There are nine approaches of TCM, including Chinese medicines (中藥), acupuncture (針灸), food therapy (食療), Qi Gong (氣功), tai chi exercise (太極), tui na (推拿), cupping (拔罐), die da (跌打), and gua sha (刮痧). Most of these therapeutic techniques in TCM have spread aboard since the sixth century BC, and in most western countries, Chinese medicines and acupuncture are the two most

With the advantages of Chinese medicines, including less side effects and greater effectiveness in some chronic diseases and cancers than Western medicines, it was gradually accepted by foreigners and now has been spread to over 160 countries [2].

ovarian cancer, breast cancer, clinical application

**1.1 Traditional Chinese medicine**

popular therapies of TCM nowadays.

Application for Female Cancer

### **Chapter 11**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

apoptosis in MCF-7 breast cancer cells. The Journal of Steroid

2007;**107**(3-5):140-148

2018;**6**(1):19

2006;**231**:43-48

[117] Konstat-Korzenny E,

Biochemistry and Molecular Biology.

Ascencio-Aragón J, Niezen-Lugo S, Vázquez-López R. Artemisinin and its synthetic derivatives as a possible therapy for cancer. Medical Science.

[118] Lai H, Singh NP. Oral artemisinin prevents and delays the development breast cancer in the rat. Cancer Letters.

**174**

## Chinese Herbal Medicine and Its Application for Female Cancer

*Rongyun Wang, Qiuhua Sun, Yifan Lin, Ling Wang, Yuan Liu, Chi Chiu Wang and Lu Li*

### **Abstract**

Chinese herbal medicines (CHMs) have been widely used to promote health and treat illnesses in daily medical care throughout Asia while mostly accepted as an alternative medical method in many nations of the western world. CHM has a unique therapeutic effect to reduce adverse effects on cancer patients caused by chemotherapy and surgery; however, we did not find any high-quality review for the claimed effects. In this review, we will summarize the history, basic theories and principles, and clinical applications of CHM for disorders, especially female cancers. Meta-analyses to evaluate the efficacy and safety of CHM in the treatment of ovarian cancer and breast cancer have been conducted. The results showed that combined CHMs and western medicines treatment (CHM-WM) had significantly relieved the symptoms and reduced the side effects after surgery and chemotherapy on both ovarian cancer and breast cancer. However, more high-quality and large-scale RCTs are necessary to confirm the efficacy and safety of CHM-WM intervention.

**Keywords:** Chinese herbal medicines, female cancer, efficacy and safety, ovarian cancer, breast cancer, clinical application

### **1. Traditional Chinese medicine and Chinese herbal medicines**

#### **1.1 Traditional Chinese medicine**

Traditional Chinese medicine (TCM) has a history that spans 5000 years and has been widely used to promote health and treat illnesses [1]. Although TCM has such wide applications as an important part in daily medical care throughout Asia, it is mostly accepted as an alternative medical method in many nations of the western world.

There are nine approaches of TCM, including Chinese medicines (中藥), acupuncture (針灸), food therapy (食療), Qi Gong (氣功), tai chi exercise (太極), tui na (推拿), cupping (拔罐), die da (跌打), and gua sha (刮痧). Most of these therapeutic techniques in TCM have spread aboard since the sixth century BC, and in most western countries, Chinese medicines and acupuncture are the two most popular therapies of TCM nowadays.

With the advantages of Chinese medicines, including less side effects and greater effectiveness in some chronic diseases and cancers than Western medicines, it was gradually accepted by foreigners and now has been spread to over 160 countries [2].

More and more foreign researchers and clinical doctors seriously have interests in it and come to China for further study.

#### **1.2 Chinese herbal medicine books**

Most Chinese medicines are derived from nature, including plants, animals, and minerals. Herbal medicines from plants are much more commonly applied than the others. In China, it is not only considered as a primary therapy for treatment but also as a supplementary therapy to promote health in general [2].

Shen Nong's *Herbal Classic* (神農本草經) [3], which is considered the oldest book on oriental medicines, roughly classified 365 species of roots, grass, and woods from plants and furs, animals, and stones into three categories (finest grade, moderate grade, and lowest grade) according to toxicity, effectiveness, and pharmacological effect of them. "Ben Cao" has been developed widely and quickly in China and has been comprehensively studied for about 2000 years. Another world famous book is *Compendium of Materia Medica* (本草綱目), which is also called the *Encyclopedia of China* [4], which considered as the most important and comprehensive review to study herbs by classification, names, property, identification, function, application, formula, and so on. It opened the door to the world for the herbal medicines in Chinese medicine since it was translated into different languages in the seventeenth century [4].

In the late nineteenth century, with the influence of foreign scientific and technical influences, Western medicine spread to China, and it has been in coexistence with Chinese medicines since then [5]. Correspondingly, the community and medical societies defined a new concept of "Chinese herbal medicines (CHMs)" from "Ben Cao" and "Chinese medicines" as different from "Western medicines" [6] to identify the corresponding medicines. After the establishment of the People's Republic China, there comes the faster development of CHM [2].

*Chinese Pharmacopeia* (中國藥典) and *Chinese Herbal Medicine* (中華本草) were published and considered as the most useful and important reference books as Bibles of the Chinese medicine. In *Chinese Pharmacopeia* over 3700 Chinese medicines were listed, while in *Chinese Herbal Medicine* over 8900 different medicinal substances were recorded. Approximately 600 Chinese herbs are widely used, while about 250 or so are commonly used in clinical practice [7].

These two Bibles gave all the details and information on individual herbs, animals, and mineral products, including formal names, different names, common names, species, source, original plant, cultivation (aquaculture) point, harvest processing, medicine and marketing, medicine identification, chemical composition, pharmacology, processing, properties, effects, application indications, compatibility, usage, dosage, precautious, preparation, clinical research, medicine theory, annals, notes, and references. They also conclude on special topics about history, resources, storage, chemistry, and pharmacology in Chinese medicines [7].

### **2. Theories and principles of Chinese herbal medicines**

#### **2.1 Basic properties of CHM**

Four gases (四氣), namely, hot (熱), warm (溫), cold (寒), and cool (涼), refer to four temperature characteristics of the herbs [2, 8]. There is another character called neutral (平), which means the existence of both hot and cold [2].

Five flavors (五味), namely, sour (酸), bitter (苦), sweet (甘), spicy (辛), and salty (咸), refer to five taste properties of the herbs [2].

**177**

*Chinese Herbal Medicine and Its Application for Female Cancer*

Lifting-dropping and floating-sinking (升降浮沉) applies the elevationelimination and outward-inward tendencies of the herbs in the body. For example, good controlling of the Qi and blood is the basic way in stroke treatment in Chinese medicine, and then a doctor may give a Chinese Thorowax root (Chai Hu) and immature bitter orange (Zhi Shi) as basic formula [2, 6, 9]. With the lifting function of Thorowax root, it can clear up the gas accumulated in the liver. Depends on the dropping effect of bitter orange, it can sort out the gas in the intestine and then

Take lotus as an example; its flower is used to prevent heat stroke, its nut is applied to treat hypertension, its root can improve gastrointestinal function, and its

As in Western medicine, medicines are often applied separately or in combination as cocktail with the same or complementary function. It is important to understand that each medicine has its own effect and function, but in most cases, instead of being prescribed individually, formulae are commonly used by TCM practitioners as therapy to different kinds of health-related problems [11].

Chinese medicines are prescribed in formulae. Based on medical knowledge and personal experience, the TCM practitioners decide the formula according to the clinical presentation [12]. In practice of CHM, the first formula is based on identified health problems according to the basic diagnosis theories, that is, the TCM practitioners will choose one basic formula (consisting of 4–20 herbs) from all traditional formulae related to this disease. Then the doctors will add some other herbal medicines into or subtract other herbal medicines from the basic formula, mostly according to their own experiences. For example, if a patient is suffering from headache, the TCM practitioner will prescribe a formula called "Yin Qiao San (銀翹散)" as basic formula [11], for the patient who is catching a cold. The practitioner will further identify if the patient needs some more medicines; such as if the patient has a heavy headache, mulberry leaf (Sang Ye, *Folium Mori*) will be added into the basic formula [11]. Sometimes, the practitioners will also make changes to the dosages of some herbal medicines or the whole formula to meet the specific needs of individual patients. For example, if the patient is a child, the doctor may

Ovarian cancer (OvC) is a malignant tumor which invades the ovarian epithelium and interstitium. Reduction surgery combined with adjuvant chemotherapy is the standard treatment for OvC patients, but the adverse effects due to chemotherapy still remain a major problem. While CHM therapy has a unique therapeutic effect to reduce side effects of chemotherapy by boosting the immune system, the

A systematic review to evaluate the efficacy and safety of CHM in the treatment of OvC after reduction surgery and adjuvant chemotherapy has been conducted. Chinese National Knowledge Infrastructure (CNKI) and PubMed up to December 31, 2018, were searched to identify relevant studies. Only randomized controlled trials (RCTs) were included, and there was no limitation on language of the publication. Data were extracted from all included studies, and meta-analysis

consider reducing the total dosage and duration of the formula.

evidence of CHM in the treatment of OvC patients is limited [13].

**3. Clinical application of Chinese herbal medicines**

**3.1 Efficacy and safety of CHM for ovarian cancer**

*DOI: http://dx.doi.org/10.5772/intechopen.90129*

make the gas flow smoothly within the body.

stem has anti-miscarriage effects [10].

**2.2 Application principles of CHM**

*Chinese Herbal Medicine and Its Application for Female Cancer DOI: http://dx.doi.org/10.5772/intechopen.90129*

Lifting-dropping and floating-sinking (升降浮沉) applies the elevationelimination and outward-inward tendencies of the herbs in the body. For example, good controlling of the Qi and blood is the basic way in stroke treatment in Chinese medicine, and then a doctor may give a Chinese Thorowax root (Chai Hu) and immature bitter orange (Zhi Shi) as basic formula [2, 6, 9]. With the lifting function of Thorowax root, it can clear up the gas accumulated in the liver. Depends on the dropping effect of bitter orange, it can sort out the gas in the intestine and then make the gas flow smoothly within the body.

Take lotus as an example; its flower is used to prevent heat stroke, its nut is applied to treat hypertension, its root can improve gastrointestinal function, and its stem has anti-miscarriage effects [10].

#### **2.2 Application principles of CHM**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

also as a supplementary therapy to promote health in general [2].

Republic China, there comes the faster development of CHM [2].

about 250 or so are commonly used in clinical practice [7].

**2. Theories and principles of Chinese herbal medicines**

salty (咸), refer to five taste properties of the herbs [2].

called neutral (平), which means the existence of both hot and cold [2].

and come to China for further study.

**1.2 Chinese herbal medicine books**

seventeenth century [4].

**2.1 Basic properties of CHM**

More and more foreign researchers and clinical doctors seriously have interests in it

Most Chinese medicines are derived from nature, including plants, animals, and minerals. Herbal medicines from plants are much more commonly applied than the others. In China, it is not only considered as a primary therapy for treatment but

Shen Nong's *Herbal Classic* (神農本草經) [3], which is considered the oldest book on oriental medicines, roughly classified 365 species of roots, grass, and woods from plants and furs, animals, and stones into three categories (finest grade, moderate grade, and lowest grade) according to toxicity, effectiveness, and pharmacological effect of them. "Ben Cao" has been developed widely and quickly in China and has been comprehensively studied for about 2000 years. Another world famous book is *Compendium of Materia Medica* (本草綱目), which is also called the *Encyclopedia of China* [4], which considered as the most important and comprehensive review to study herbs by classification, names, property, identification, function, application, formula, and so on. It opened the door to the world for the herbal medicines in Chinese medicine since it was translated into different languages in the

In the late nineteenth century, with the influence of foreign scientific and technical influences, Western medicine spread to China, and it has been in coexistence with Chinese medicines since then [5]. Correspondingly, the community and medical societies defined a new concept of "Chinese herbal medicines (CHMs)" from "Ben Cao" and "Chinese medicines" as different from "Western medicines" [6] to identify the corresponding medicines. After the establishment of the People's

*Chinese Pharmacopeia* (中國藥典) and *Chinese Herbal Medicine* (中華本草) were

published and considered as the most useful and important reference books as Bibles of the Chinese medicine. In *Chinese Pharmacopeia* over 3700 Chinese medicines were listed, while in *Chinese Herbal Medicine* over 8900 different medicinal substances were recorded. Approximately 600 Chinese herbs are widely used, while

These two Bibles gave all the details and information on individual herbs, animals, and mineral products, including formal names, different names, common names, species, source, original plant, cultivation (aquaculture) point, harvest processing, medicine and marketing, medicine identification, chemical composition, pharmacology, processing, properties, effects, application indications, compatibility, usage, dosage, precautious, preparation, clinical research, medicine theory, annals, notes, and references. They also conclude on special topics about history, resources, storage, chemistry, and pharmacology in Chinese medicines [7].

Four gases (四氣), namely, hot (熱), warm (溫), cold (寒), and cool (涼), refer to four temperature characteristics of the herbs [2, 8]. There is another character

Five flavors (五味), namely, sour (酸), bitter (苦), sweet (甘), spicy (辛), and

**176**

As in Western medicine, medicines are often applied separately or in combination as cocktail with the same or complementary function. It is important to understand that each medicine has its own effect and function, but in most cases, instead of being prescribed individually, formulae are commonly used by TCM practitioners as therapy to different kinds of health-related problems [11].

Chinese medicines are prescribed in formulae. Based on medical knowledge and personal experience, the TCM practitioners decide the formula according to the clinical presentation [12]. In practice of CHM, the first formula is based on identified health problems according to the basic diagnosis theories, that is, the TCM practitioners will choose one basic formula (consisting of 4–20 herbs) from all traditional formulae related to this disease. Then the doctors will add some other herbal medicines into or subtract other herbal medicines from the basic formula, mostly according to their own experiences. For example, if a patient is suffering from headache, the TCM practitioner will prescribe a formula called "Yin Qiao San (銀翹散)" as basic formula [11], for the patient who is catching a cold. The practitioner will further identify if the patient needs some more medicines; such as if the patient has a heavy headache, mulberry leaf (Sang Ye, *Folium Mori*) will be added into the basic formula [11]. Sometimes, the practitioners will also make changes to the dosages of some herbal medicines or the whole formula to meet the specific needs of individual patients. For example, if the patient is a child, the doctor may consider reducing the total dosage and duration of the formula.

### **3. Clinical application of Chinese herbal medicines**

#### **3.1 Efficacy and safety of CHM for ovarian cancer**

Ovarian cancer (OvC) is a malignant tumor which invades the ovarian epithelium and interstitium. Reduction surgery combined with adjuvant chemotherapy is the standard treatment for OvC patients, but the adverse effects due to chemotherapy still remain a major problem. While CHM therapy has a unique therapeutic effect to reduce side effects of chemotherapy by boosting the immune system, the evidence of CHM in the treatment of OvC patients is limited [13].

A systematic review to evaluate the efficacy and safety of CHM in the treatment of OvC after reduction surgery and adjuvant chemotherapy has been conducted.

Chinese National Knowledge Infrastructure (CNKI) and PubMed up to December 31, 2018, were searched to identify relevant studies. Only randomized controlled trials (RCTs) were included, and there was no limitation on language of the publication. Data were extracted from all included studies, and meta-analysis

was performed with ReviewManager 5.3. The study quality was assessed, and pooled risk ratios (RR) or mean difference (MD) with 95% CIs were used to evaluate the efficacy and safety of CHM.

A total of 18 RCTs involving 975 participants were included. There was no placebo, no treatment, and CHM alone. Compared with Western medicine (WM) alone, Chinese herbal medicine combined with WM (CHM-WM) significantly improved TCM syndromes and symptoms, KPS scores, CD4 counts, CA125 levels, and 3-year survival rate (P < 0.05). Incidences of gastrointestinal reactions, marrow depression, and urinary system symptoms were significantly lower in CHM-WM group than in WM group (P < 0.01). There was no significant difference in CD3 counts, CD8 counts, quality of life, liver function, and peripheral neuropathy between the two groups (P > 0.05).

The systematic review indicated that CHM combined with WM is effective and safe as a treatment for OvC patients after reduction surgery and adjuvant chemotherapy. However, more high-quality and large-scale RCTs are needed to confirm the efficacy and safety of CHM intervention.

#### **3.2 Efficacy and safety of CHM for breast cancer**

Breast cancer is a disease in which malignant (cancer) cells form in the tissues of the breast. Surgery combined with adjuvant chemotherapy is considered as the standard treatment for breast cancer patients, but the adverse effects after surgery and chemotherapy still cause big problems. While CHM therapy has a unique therapeutic effect to reduce side effects of chemotherapy and surgery by boosting immune system, we did not find any high-quality review for the claimed effects of CHM-WM treatment on breast cancer patients. A systematic review to evaluate the efficacy and safety of CHM-WM treatment in patients with breast cancer has been conducted.

Chinese National Knowledge Infrastructure (CNKI) and PubMed databases (up to August 31, 2019) were searched to identify relevant clinical studies. Only randomized controlled trials (RCTs) were included, and there was no limitation on language of the publication. Data were extracted from all included studies, and meta-analyses were performed with Review Manager 5.3. The study quality was assessed, and pooled risk ratios (RR) or mean difference (MD) with 95% CIs were used to evaluate the efficacy and safety of treatments.

A total of 22 RCTs involving 1256 participants was included. Compared with WM alone, CHM-WM significantly improved skin flap necrosis and upper limb lymphedema after breast cancer surgery (P < 0.05). Incidences of nausea and vomiting, constipation, marrow depression, and hot flashes were significantly lower in CHM-WM group than in WM group (P < 0.05). There was no significant difference in tumor metastasis and recurrence, survival rate, platelet counts, and CD3 and CD4 levels between the two groups (P > 0.05).

Meta-analysis results showed that the combination of CHMs and WMs was an effective and safe therapy for patients with breast cancer after surgery and chemotherapy. However, more high-quality and large-scale RCTs are necessary to confirm the efficacy and safety of CHM-WM intervention.

**179**

**Author details**

Hangzhou, China

Hangzhou, China

Hong Kong, China

Rongyun Wang1†, Qiuhua Sun1†, Yifan Lin2

Chi Chiu Wang4,5 and Lu Li4,5,6\*

Hong Kong, Hong Kong, China

† These authors contributed equally.

provided the original work is properly cited.

, Ling Wang2

1 School of Nursing, Zhejiang Chinese Medical University, Hangzhou, China

2 The First College of Clinical Medicine, Zhejiang Chinese Medical University,

3 The First School of Clinical Medicine, Lanzhou University, Lanzhou, China

4 College of Basic Medical Sciences, Zhejiang Chinese Medical University,

5 Department of Obstetrics and Gynaecology, The Chinese University of

6 Institute of Chinese Medicine, The Chinese University of Hong Kong,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: lucia.lu.lee@zcmu.edu.cn

, Yuan Liu3

,

*Chinese Herbal Medicine and Its Application for Female Cancer*

*DOI: http://dx.doi.org/10.5772/intechopen.90129*

## **Author details**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

ate the efficacy and safety of CHM.

thy between the two groups (P > 0.05).

the efficacy and safety of CHM intervention.

**3.2 Efficacy and safety of CHM for breast cancer**

used to evaluate the efficacy and safety of treatments.

CD4 levels between the two groups (P > 0.05).

the efficacy and safety of CHM-WM intervention.

was performed with ReviewManager 5.3. The study quality was assessed, and pooled risk ratios (RR) or mean difference (MD) with 95% CIs were used to evalu-

A total of 18 RCTs involving 975 participants were included. There was no placebo, no treatment, and CHM alone. Compared with Western medicine (WM) alone, Chinese herbal medicine combined with WM (CHM-WM) significantly improved TCM syndromes and symptoms, KPS scores, CD4 counts, CA125 levels, and 3-year survival rate (P < 0.05). Incidences of gastrointestinal reactions, marrow depression, and urinary system symptoms were significantly lower in CHM-WM group than in WM group (P < 0.01). There was no significant difference in CD3 counts, CD8 counts, quality of life, liver function, and peripheral neuropa-

The systematic review indicated that CHM combined with WM is effective and safe as a treatment for OvC patients after reduction surgery and adjuvant chemotherapy. However, more high-quality and large-scale RCTs are needed to confirm

Breast cancer is a disease in which malignant (cancer) cells form in the tissues of the breast. Surgery combined with adjuvant chemotherapy is considered as the standard treatment for breast cancer patients, but the adverse effects after surgery and chemotherapy still cause big problems. While CHM therapy has a unique therapeutic effect to reduce side effects of chemotherapy and surgery by boosting immune system, we did not find any high-quality review for the claimed effects of CHM-WM treatment on breast cancer patients. A systematic review to evaluate the efficacy and safety of CHM-WM treatment in patients with breast cancer has been

Chinese National Knowledge Infrastructure (CNKI) and PubMed databases (up to August 31, 2019) were searched to identify relevant clinical studies. Only randomized controlled trials (RCTs) were included, and there was no limitation on language of the publication. Data were extracted from all included studies, and meta-analyses were performed with Review Manager 5.3. The study quality was assessed, and pooled risk ratios (RR) or mean difference (MD) with 95% CIs were

A total of 22 RCTs involving 1256 participants was included. Compared with WM alone, CHM-WM significantly improved skin flap necrosis and upper limb lymphedema after breast cancer surgery (P < 0.05). Incidences of nausea and vomiting, constipation, marrow depression, and hot flashes were significantly lower in CHM-WM group than in WM group (P < 0.05). There was no significant difference in tumor metastasis and recurrence, survival rate, platelet counts, and CD3 and

Meta-analysis results showed that the combination of CHMs and WMs was an effective and safe therapy for patients with breast cancer after surgery and chemotherapy. However, more high-quality and large-scale RCTs are necessary to confirm

**178**

conducted.

Rongyun Wang1†, Qiuhua Sun1†, Yifan Lin2 , Ling Wang2 , Yuan Liu3 , Chi Chiu Wang4,5 and Lu Li4,5,6\*

1 School of Nursing, Zhejiang Chinese Medical University, Hangzhou, China

2 The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China

3 The First School of Clinical Medicine, Lanzhou University, Lanzhou, China

4 College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China

5 Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China

6 Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China

\*Address all correspondence to: lucia.lu.lee@zcmu.edu.cn

† These authors contributed equally.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

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[2] Li JB. Zhong Yi Xue. 6th ed. Beijing, China: People's Health Publishing House; 2005. pp. 1-135, 186, 187

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pp. 1-233

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fonc.2019.00730

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ShenNong's Herbal Classic (3 Volumes). 1st ed. Shenyang, China: Liaoning Science and Technology Press; 1995

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*Edited by Bassam Abdul Rasool Hassan*

This book is focused on clarifying the anticancer effects (i.e., apoptotic, antiproliferative, antimetastatic, antiangiogenic) and mechanisms of most of the medicinal plants found in the world against solid and/or hematological cancers.

Published in London, UK © 2020 IntechOpen © mychadre77 / iStock

Medicinal Plants - Use in Prevention and Treatment of Diseases

Medicinal Plants

Use in Prevention and Treatment of Diseases

*Edited by Bassam Abdul Rasool Hassan*