Plant-Based Drugs as an Adjuvant to Cancer Chemotherapy

*Lakshmi Mohan*

## **Abstract**

Humans have turned to natural products, obtained from plants, animals and aquatic life for treating diseases since time immemorial. Modern medicine is based on ancient wisdom transferred over generations. Drug development relies mainly on natural sources. Herbal medicines are making a comeback due to lower side effects, and positive results in the long term when compared to synthetic drugs. The current drug discovery process relies on identifying traditional medicines followed by Bioactivity-guided fractionation to isolate significant lead molecules. Plants have a history of long-term use by humans and hence it can be presumed that the bioactive compounds obtained from plants will have low human toxicity. There exists a huge potential for discovering new antitumor drug leads by screening natural products either in the form of crude extracts purified phytochemicals which have already been described in the literature. The fact that phytochemicals like paclitaxel, vinblastine, vincristine and camptothecin are being successfully used in clinical practice and several others like combretastatin and noscapine are in different stages of clinical trials implies the importance of plants in cancer chemotherapy.

**Keywords:** plant, medicinal plants, cancer, alternative therapy, synergy

## **1. Introduction**

*"Until man duplicates a blade of grass, nature can laugh at his so-called scientific knowledge. Remedies from chemicals will never stand in favourable comparison with the products of nature, the living cell of the plant, the final result of the rays of the sun, the mother of all life." - Thomas Alva Edison.*

The global cancer burden has escalated to 9.6 million deaths and 18.1 million new cases in 2018. It is a fact that one in 5 men and one in 6 women around the world develop cancer during their lifetime, and it kills one in 8 men and one in 11 women [1]. Cancer continues to be the second leading cause of death globally, the first being cardiovascular diseases. Patients with cancer normally have a poor prognosis in low and middle-income countries such as India, due to a lack of awareness about the disease, delayed diagnosis, and inadequate or no access to affordable therapeutic services when compared with patients in high-income countries. The number of incident cancer cases in India is estimated to be 1 069 000 in 2016. Access to critical cancer treatment is also very low in the country. It is the need of the day to find a natural, affordable treatment strategy for cancer [2].

The conventional modality for cancer treatment involves the use of surgery, radiation and chemotherapy either alone or in combination with the others. Each of the treatment modality offers its risks and benefits. Although chemotherapeutic medicines are toxic and have a very narrow therapeutic index, they offer a transient relief from symptoms and help prolong life especially in the case of cancers where surgery and radiation is not a feasible mode of treatment like leukaemia and lymphomas. Chemotherapy is a systemic treatment because it can be used to treat cancer anywhere in the body when compared to local treatment approaches. The chemotherapeutic agents that are currently used in clinical practice lack specificity to the cancer cells and could damage the healthy cells causing adverse side effects. Toxicity and severe side effects continue to be significant setbacks involved in chemotherapeutic approaches to the treatment of cancer. To overcome the limitations, scientists across the globe are searching for new anticancer agents with more specificity and fewer side effects. Many recent studies have found that an extensive array of natural substances exert selective toxicity against cancer cells by selectively eliminating them causing less harm to the normal cells [3].

Cragg and Newman et al. have identified that nearly 5% out of the 1031 new chemical entities approved for use as drug between 1981 and 2002, by the US FDA (Food and Drug Administration) were natural products and 23% were derived from natural products [4]. Some well-known plant secondary metabolites used as medicine are paclitaxel, vinblastine, vincristine, artemisinin, atropine, inulin, digoxin, morphine and codeine, and quinine [5, 6]. Normal metabolism in plants produces a variety of chemical compounds. The primary metabolites are found ubiquitously like fats and sugars whereas the secondary metabolites are more specific to a particular genus or species. An advantage of plant metabolites is that apart from serving as functional drugs, they can be used as lead molecules for the synthesis of derivatives or synthetic molecules with the active pharmacophore.

#### **2. Cancer and metastasis**

The term 'cancer' refers to a range of diseases in which abnormal cells proliferate and spread uncontrollably in the body [7]. Under normal conditions, cells grow and multiply systematically to form organs and tissues that have a specific function. Occasionally, however, they multiply in an uncontrolled manner after developing a random genetic mutation or due to the influence of a carcinogen and form a mass known as a tumour or neoplasm that has no physiological function. It was Hippocrates (460–370 B.C.), the Greek physician who used the names 'carcinos' and 'carcinoma' to define non-ulcer forming and ulcer-forming tumours. In Greek, carcinos and carcinoma mean 'crab'; and the disease was named so because the finger-like projections extending from cancer resemble a crab in shape. Carcinomas, a type of cancer which arises from epithelial cells, is the most common type of cancer affecting people today. The first abnormality concerning cell maturation to be evident microscopically is known as dysplasia. This, in turn, leads to architectural chaos, irregularity in the nucleus, augmented and abnormal mitoses, and an increase in the number of apoptotic cells.

Tumours in the body can be benign or malignant. Benign tumours are those which do not invade other tissues or spread to other parts of the body. Malignant tumours, however, can grow in an uncontrolled way and by a process known as metastasis, can spread within the body. Even though all tumours are diverse and heterogeneous, they share the capacity to proliferate beyond the constraints that limit the growth of healthy tissue [7]. They can spread by direct local invasion,

vascular spread, cerebrospinal fluid (CSF) spread, transcoelomic (peritoneal or pleural) spread or lymphatic spread.

Modifications in the regulation of some crucial pathways that control cell proliferation (cell cycle) and survival (apoptosis) are responsible for creating all tumours [8]. The modifications include the loss of function of the tumour suppressor gene, oncogenic transformations, as well as modifications in the signal transduction pathways which leads to an augmented proliferation in response to external/mitogenic signals. As such, tumour-associated mutations in many of these pathways result in the alteration of the necessary regulatory mechanisms that control the mammalian cell cycle.

## **3. Cancer therapy**

Surgery remains one of the foremost treatments for cancer. It has been mentioned by Roman doctor Gallien as a means of treating cancer as early as the 2nd century. It was followed by radiation therapy using radium and other diagnostic machines using relatively less voltage. Although the present methodology and the equipment for delivery of radiation therapy have improved allowing the obliteration of malignant tumours with great precision, this mode of therapy is limited by severe side effects and a restricted capacity to distinguish between healthy and tumour cells. Furthermore, both radiation and surgery are not beneficial in cases of advanced metastatic cancers.

Traditional treatments for cancer such as chemotherapy (e.g. anti-metabolites, alkylating agents, topoisomerase inhibitors) and radiation therapy were developed based upon the observation that transformed cells multiply at a higher rate when compared to normal cells. For example, ionising radiation results in DNA damage which, after multiple cell divisions, leads to errors in transcription and translation, eventually resulting in cell death [9]. In the same way, cytotoxic chemotherapy interferes with microtubule organisation, which is essential for mitosis and in due course, affects cell survival [10]. The same is true for various haematopoietic malignancies, however, as little as 5% of some solid tumours consist of rapidly proliferating, and therefore, susceptible cells. Hence, only a small subset of cancers such as Hodgkin's lymphoma, testicular cancer, acute lymphoid leukaemia and non-Hodgkin's lymphoma are routinely cured using these agents [11]. This is largely because therapies that are targeted against rapidly proliferating cells cause the death of normal tissues which also show enhanced proliferation rates, such as the gastrointestinal (GI) tract, bone marrow and the hair follicles [12].

## **4. Drug resistance**

The development of drug resistance is also a major obstacle in patients receiving prolonged chemotherapeutic treatment. Clinical resistance to anticancer agents can occur at the time of drug introduction, as well as during treatment and following relapse [13]. Although various resistance mechanisms have been described, such as insufficient activation of the drug, utilisation of alternate metabolic pathways, mutations in the p53 gene and overexpression of the Bcl-2 gene family, the most intensely studied has been the decreased accumulation of drugs in cells, which is the leading cause of multi-drug resistance [14]. Such resistance is indicated by a failure to respond to a range of chemotherapeutic agents, many of which are structurally dissimilar and do not share a common intracellular target. The

mechanism responsible for Multidrug resistance in mammalian cells involves the overexpression of a 170 kDa cell surface, energy-dependent plasma membrane glycoprotein (P-gp) encoded on the MDR1 gene [15]. The physiological role of P-gp is the protection of cells against environmental toxins and works by exporting drugs outside of mammalian cells, thereby lowering the intracellular drug concentration less than the toxic threshold [16]. However, the chemotherapy of cancer, as compared with that of bacterial disease, poses a critical problem. Microorganisms are quantitatively and qualitatively different from human cells, while, cancer cells and normal cells are so similar that it has proved difficult to find general, exploitable biochemical differences between them. This is exemplified by the number of drugs selected for preclinical or clinical testing, based on their activity in experimental animal systems, which do not become clinically useful agents due to their severe or unpredictable toxicity towards normal cells, or because they lack any therapeutic advantage. The prevalence of MDR and systemic toxicity associated with currently administered cancer chemotherapies therefore suggest the need for alternative possibilities to be investigated to find new and worthy therapeutic agents.

## **5. Apoptosis and the need for apoptotic inducers**

The process of homeostasis in multicellular organisms is strongly regulated by a process known as PCD (programmed cell death) or apoptosis. When cells obtain diverse indications for growth they generally die. This happens when certain developmental processes call for cell division but there are no external growth signals when a growth-related gene, e.g. c-myc gets highly expressed but the cellular environment lacks nutrient content, and in the presence of a toxic xenobiotic and the cell dies by a process termed apoptosis. The term 'apoptosis' was used for the first time in 1972 in literature, to describe a structurally-distinctive method of cell death which caused the loss of cells within live tissues [17].

There are inherent cellular programs that direct a cell into self-destruction. Several occurrences helped establish this; e.g. in the nematode, *Caenorhabditis elegans*, it has been discovered observed that a set of 113 cells is destined for programmed cell death in the hermaphrodite form of the worm during embryogenesis, and a different set of 18 cells later in life, forming a total of 131 cells [18].

The key features include blebbing and shrinkage of the cytoplasm, conservation of cellular organelle structure, involving the mitochondria and the condensation and margination of chromatin, although all cell types do not show all of these characteristics. These changes are a consequence of a developmental program for cell death which is activated by the deficiency of a growth factor, or by the presence of a xenobiotic compound such as a therapeutic anticancer drug. The morphological criteria are still the most important when complex cell populations, such as tissues, are examined, and overall cell shrinkage and nuclear condensation are the easiest to recognise [19].

The discovery of about 30 novel molecules whose functions are completely related to the initiation or control of apoptosis has been made over the last decade. Another 20 molecules, associated with essential roles in cell signalling and DNA transcription, replication or repair, have been established as effectors of apoptosis regulation. The rate of apoptosis influences the lifespan of cells in the human body, both healthy and cancer cells. Thus, the modulation of apoptosis is useful in the deterrence, management and therapy of cancer. Synthesis of novel compounds based on existing templates continues to be an indispensable aspect of research. Natural products are capable of providing such templates. Latest studies on tumour inhibitory compounds originating from plants have given rise to a remarkable group *Plant-Based Drugs as an Adjuvant to Cancer Chemotherapy DOI: http://dx.doi.org/10.5772/intechopen.94040*

of unique structures. Moreover, epidemiological findings confirm the theory that following a diet containing plenty of fruits and vegetables which are key sources of micronutrients and phytochemicals, reduces the risk of acquiring cancer [20]. It has also been reported that some products from plants bring about apoptosis in neoplastic cells alone and not in normal cells [21].

There have been reports confirming the role of apoptosis as an essential mode of action for several anti-tumour agents, such as alkylating agents including the widely used cisplatin and 1,3- bis (2-chloroethyl)-1-nitrosourea (BCNU) [22], ionising radiation [23], topoisomerase inhibitor etoposide, taxol [24], the tumour necrosis factor (TNF) [25], and N-substituted benzamides like 3-chloroprocainamide and metoclopramide [26].

#### **6. Plant secondary metabolites used IN conventional medicine**

The WHO (World Health Organisation) defines a medicinal plant as a plant whose one or more parts, has constituents which can be applied for therapeutic purposes, or can act as precursors for chemical or pharmacological semi-synthesis. The parts of these medicinal plants such as the roots, tubers, barks, stems, leaves, flowers, seeds and fruits/grains, contains metabolites that are therapeutically active and are used to control or treat a disease condition.

Such non-nutritional chemical compounds or bioactive components in plants are called phytochemicals, the word –'phyto'- from Greek, meaning 'plant'. These phytoconstituents are responsible for protecting the plant against pest infestation or microbial infections [27]. A large variety of phytochemicals have been isolated and characterised from familiar sources including vegetables such as onion and broccoli, fruits like apples and grapes, spices such as nutmeg, pepper and turmeric, brews such as green tea, oolong tea and red wine [28], which possess strong antioxidant properties. These antioxidants in chemoprevention and treatment of cancer and many more diseases by defending cells from damage by highly reactive oxygen compounds called 'free radicals'. The common classes of plant secondary metabolites which have found their way into traditional and modern medicine include.

Quercetin, quercitrin and kaempferol are common flavonoids present in approximately seventy per cent of all plants. Flavonoids vary notably in their antiproliferative effectiveness depending on their structure. Kuntz et al. discovered that baicalein and myricetin induced apoptosis in Caco-2 and HT-29 cells [29]. Flavone, flavanone, flavonol, and isoflavone classes of flavonoids possess anti-proliferative effects in various cancer cell lines. Tangeretin found in the peel of tangerine is used extensively in Kampo medicines in Japan for treating cancer [21].

Solamargine, derived from a Chinese herb, *Solanum incanum*, has been noted to bring about apoptosis in human hepatocyte (Hep-3B) cells and normal skin fibroblast cells [30]. The alkaloids isolated from *Tiliacora racemosa* root with several bis-benzylisoquinoline alkaloids induced apoptosis in K-562 cells. Camptothecin (CPT), extracted from the stem wood of a Chinese tree, *Camptotheca acuminata Decsne, Nyssaceae*, works as a topoisomerase I inhibitor and induces apoptosis in PLB-985 (a human leukaemia cell line) cells [31]. The widely popular alkaloids Vinblastine and vincristine are obtained from the Madagascar periwinkle, *Catharanthus roseus* (previously called *Vinca rosea*).

A new cytotoxic proteoglycan, which is related to the family of arabinogalactan proteins, isolated from the saffron plant (*Crocus sativus L*.) exhibited induction of apoptosis in cultured macrophages with a lesser non-cytotoxic concentration increasing the DNA laddering effect in apoptotic cells [32].

A phytopreparation made from *Viscum album L*., is currently being used as an adjuvant in cancer therapy and is found to stimulate the immune system by improving the number and activity of neutrophils and NK cells [33]. The formulation has various toxic proteins including viscotoxins (VT) and mistletoe lectins (ML); induces the synthesis of cytokines such as IFN-g,TNF-a, IL-6 and 1 L-1 and exhibits cytostatic and cytotoxic effects on human lymphocytes and cultured tumour cells alike.

## **7. Why use plant-based drugs?**

Plants are an important part of nature's reservoir of medicinal agents and it is safe to say that they are nearly devoid of the side effects generally caused by synthetic drugs and chemical agents [34]. The WHO (World Health Organisation) reports that traditional medicine remains the chief mode of the treatment availed by 75–80% of the world's total population for primary health care, particularly in developing countries. This can be attributed to improved compatibility with the human body, better cultural acceptability, and reduced or practically no side-effects [35, 36].

Although several compounds isolated from plants are in the process of being thoroughly tested for their anticancer properties, it is becoming acknowledged that the medicinal effects of plants are due to a complex interaction of the combination of compounds present in the whole plant (additive/synergistic and/or antagonistic) rather than the single constituents [27].

The review of the literature reveals that phytochemicals present in normal fruit and vegetables have harmonising and overlapping mechanisms of action, such as the modulation of detoxification enzymes, stimulation of the immune system, scavenging of free radicals, regulation of gene expression, hormone metabolism, antibacterial and antiviral properties. Bioactive plant extracts are valuable resources which aid in the development of less toxic, more efficient drugs to manage the progression of cancer.

A major problem concerning cancer chemotherapy is the development of resistance to cytotoxic agents. Overcoming multidrug resistance requires research into new antineoplastic agents. In this regard, natural products acquired from plants have shown to have high potential as drug reservoirs [37]. According to the WHO, around 80% of the population in developing countries rely on traditional medicines, mostly derived from plants for primary health care. The modern pharmacopoeia contains a minimum of 25% drugs which are derived from plants and several others which are synthetic analogues [38]. Hence, fighting cancers with natural compounds derived from plants present a very favourable alternative.

Phytochemicals display structural diversity and contain scaffolds tailored to bind and inhibit the functions of several key proteins. They have more chiral centres and varied ring systems when compared to synthetic drugs. This complexity is responsible for increasing its target selectivity thereby reducing non-specific binding and adverse side effects [39].

#### **8. Drug combinations and synergy**

Drug combinations are widely used to treat deadly diseases such as AIDS and cancer. The main intention is to accomplish a reduction in dose and toxicity, synergistic therapeutic effect and lessen or delay the induction of drug resistance.


#### *Plant-Based Drugs as an Adjuvant to Cancer Chemotherapy DOI: http://dx.doi.org/10.5772/intechopen.94040*


#### **Table 1.**

*Combinations studies with anti-cancer drugs in clinical practice.*

*Plant-Based Drugs as an Adjuvant to Cancer Chemotherapy DOI: http://dx.doi.org/10.5772/intechopen.94040*

Synergistic interactions are essential in phytomedicine and explain the effectiveness of extremely low doses of active constituents in herbal formulations. Traditional medicine works on the idea that a whole or partly purified plant extract offers improvements over a single isolated ingredient. Synergism also leads to toxicity reduction and minimization of resistance. Though vinblastine is successful clinically by itself [40, 41], its use in combination with other anticancer agents is now under evaluation, mostly for the management of recurrent or advanced cancers that are resistant to conventional chemotherapy. The occurrence of clinical drug resistance has emphasised the need to search for novel chemotherapeutic drugs and better combinations among these agents. Typically, synergy is considered to be greater than additive therapeutic effects when compared with the efficacy of each drug by itself. Recently, combination therapies being tested make use of drugs with different mechanisms of action, under the rationale that targeting two separate pathways will result in improved cytotoxicity, whether additive or synergistic.

Several researchers have tried to enhance the potential of known anti-cancer agents like vinblastine and paclitaxel by the virtue of combination therapy with cisplatin, etoposide and doxorubicin. **Table 1** gives a list of the combination studies performed on plant secondary metabolites with anti-cancer drugs in clinical practice which showed synergistic activity.

### **9. Future perspectives**

Cancer cells have evolved multiple mechanisms to evade apoptosis and escape to other sites. Phytomedicine and ethnopharmacology have proved to be very effective in the prevention and treatment of human ailments. Plant extracts have several components with diverse possible intracellular targets. From literature, it is evident that plants have a long history of oral use in traditional medicine and hence, are considered safe and non-toxic and there lies a huge potential in developing crude whole plant extracts for the treatment of cancer, alone or in a combination with other drugs in clinical practice. It is also advisable to explore the potential of these plants as chemopreventive agents because of their antioxidant and free radical scavenging activity. However, before these plant metabolites can be used for cancer prevention or therapy, they must be subject to further testing which should include in vivo studies in animal models and clinical trials (randomised double-blind) in human subjects.

#### **Author details**

Lakshmi Mohan Department of Food Technology, Saintgits College of Engineering, Kerala, India

\*Address all correspondence to: lakshmi.mohan@saintgits.org

© 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.

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## **Chapter 17**

## Impact of Shodhana on *Semecarpus anacardium* Nuts

*Pratap Kumar Sahu and Prashant Tiwari*

## **Abstract**

*Semecarpus anacardium* is classified in Ayurveda under the category of toxic plants. However, this toxic plant is reported to possess anti-inflammatory activity, anti-arthritic effect, antioxidant activity, antimicrobial activity, anti- carcinogenic activity, hypoglycemic activity, cardioprotective, hepatoprotective, neuroprotective, and hypolipidemic activity etc*.* All these activities are attributed to its various constituents like phenolic compounds, flavonoids, carbohydrates, alkaloids, steroids, etc. In Ayurveda, a series of pharmaceutical procedures which converts a poisonous drug into a safe and therapeutically effective medicine is termed as Shodhana. Shodhana improves the yield, decreases the phenolic and flavonoid content; and converts toxic urushiol into nontoxic anacardol derivative thereby reducing toxicity of nuts of *Semecarpus anacardium*. There are reports of alteration in pharmacology and phytochemistry of nuts of *Semecarpus anacardium* due to Shodhana.

**Keywords:** Shodhana, *Semecarpus anacardium*, nuts, ayurvedic, toxic, urushiol, anacardol

## **1. Introduction**

Ayurveda is proven to be the ancient traditional way of treatment in India, which is fully based on philosophical, experimental and practical concepts. It includes the use of indigenous drugs which have been preferred by many pharmaceutical industries towards a novel strategy for natural drug discovery. Ayurvedic proven concepts signifies more on human health and disease that recommend the use of herbal enriched compounds as special diets. However, some herbal compounds may have toxicity besides their therapeutic potential if used improperly [1].

There are so many plants which are identified as poisonous and semi-poisonous in Ayurveda. Plants like Atsanabha (Aconitum species), nux-vomica, *Acorus calamus*, *Semecarpus anacardium*, Strychnos, *Abrus precatorius* etc., are the most known examples of toxic plants. These plants are known for their hidden medicinal values and broadly accepted by the Indian Ayurvedic system of medicine. These plants are still used in Indian system of development of medicine for treatment. Aconite, strychnine, β–asarone, bhilawanols, abrin are some of the toxic components present in these plants [2].

*Shodhana* is the purificatory measure used in Ayurveda to purify toxic medicinal plants (*upavishadravyas*), by various pharmaceutical procedures like soaking, rubbing and washing etc. with specific medias like *gomutra* (cow's urine), *godugdha* (cow's milk) etc. Poisonous plants are subjected to *shodhanasanskara* (purification

process), before their therapeutic use. This process reduces toxicity of poisonous plant considerably and keeps it at required optimum level. Physico-chemical changes and reduction of the toxic chemicals from the poisonous plants like strychnine, brucine in *kupilu* and scopolamine in *dhattura* have been reported [3].

*Bhallataka* (*Semecarpus anacardium* Linn; Anacardiaceae) fruit is one of the *upavishadravyas* (semi poisonous drugs). Its importance and utility is increasing day by day because of its therapeutic significance in many a diseases including cancer. Though the fruits of *Bhallataka* has many therapeutic values, pharmacies are scared to use this drug because of its irritant vesicating nature. If juice of *Bhallataka* (even in traces) comes in contact with body, produces severe *daha* (burning sensation), and *Vrana* (ulcer). When it comes in contact with face, it produces acute burning sensation with *shotha* (inflammation) and *Visarpa* (skin disease). The fruit contains tarry oil which causes contact dermatitis. Medically it is very well recognized as Urushiol induced contact dermatitis because the chemical Urushiol is responsible for dermatitis. If this vesicant nature is removed, the drug could be a good source for pharmaceutical industries in manufacturing many formulations containing *Bhallataka* as an ingredient [2, 4].

Ayurveda advocates *bhallataka* after *shodhana* (purificatory procedures). Though there are different *shodhana* methods mentioned in Ayurveda, the *shodhana* method mentioned in the text *Rasamrutam* was adopted and quoted in (The Ayurvedic Pharmacopeia of India) (API) and the Ayurvedic formularly of India (AFD). The procedure is soaking the fruits in cow's urine, cow's milk and rubbing it in brick powder [5]. It is reported that Rf values change in *shodhita* samples of *Bhallataka* when compared to raw *bhallataka* [3].

## **2.** *Semecarpus anacardium*

This is a native of India. It is known as bhallatak in India and "marking nut" by Europeans. *Semecarpus anacardium* plant (**Figure 1**) is widely available in sub-Himalayan province, tropical and central part of our country India. It is known as a deciduous tree; medium in size. Height of the tree is normally 12–15 m. Leaves are large and simple about 60 cm long and 30 cm wide. The color of bark is deep brown and is quite rough in structure. The flowers are dull greenish in color [6].

**Figure 1.** Semecarpus anacardium *plant and its nuts.*

*Impact of Shodhana on* Semecarpus anacardium *Nuts DOI: http://dx.doi.org/10.5772/intechopen.94189*

**Figure 2.** Semecarpus anacardium *(Bhallatak) nuts.*

Abundantly the plant is found in Odisha, Chittagong, central India and Northern Australia [7]. The color of fruit is black when ripe as well as smooth and shiny in texture (**Figure 2**). The fruit is generally categorized as toxic and the integral part of the fruit i.e. nut is about 1 inch long in size [8].

## **3. Active principles of** *Semecarpus anacardium*

The active principles present in *S. anacardium* Linn. are given in **Table 1** and their structures are presented in **Table 2**. Bhilawanols, phenolic compounds, [9, 10] biflavonoids, sterols and glycosides [11] are proven to be the most significant components of *S. anacardium* Linn. An alkaloid, Bhilawanol, has been identified as isolated from oil and seeds of *S. anacardium*. Bhilawanol is a mixture of cis and trans isomers of urushiol. Bhilawanol is isolated from oil of nuts. It is a mixture of phenolic compounds like 1, 2-dihydroxy-3 (pentadecadienyl-8, 11) benzene and 1, 2- dihydroxy-3 (pentadecadienyl-8<sup>0</sup> , 11<sup>0</sup> ) –benzene [10]. Bhilawanol on catalytic reduction absorbs one mole of hydrogen to give hydrourushiol (3-pentadecylcatechol) [12, 13]. When the phenolic compounds are exposed to the air, then they get oxidized to Quinones. When the oil is kept under nitrogenoxidation process can be prevented. Nut shells contain several biflavones [14], jeediflavanone [15, 16], semecarpuflavan and gulluflavone [17–19] (**Table 1**).

## **4. Uses of** *Semecarpus anacardium*

It has been reported for wide arena of ethno-pharmacological activities. Researchers have identified SA nuts extracts for potent pharmacological actions. Most of these studies are pre-clinical studies. Their clinical efficacy is yet to be reported. The list of health disorders against which *Semecarpus anacardium* has a potential to be used is given in **Table 3**. The possible mechanism of action is also described.

#### **4.1 Analgesic and anti-inflammatory effect**

There are reports of analgesic [20] and anti-inflammatory [21, 22] activity by *Semecarpus anacardium*. Biflavonoid like tetrahydroamentoflavone (THA) showed significant COX-1 and COX-2 inhibition *in vitro.* THA may be responsible for its


#### **Table 1.**

*Phytoconstituents present in* Semecarpus anacardium.

## *Impact of Shodhana on* Semecarpus anacardium *Nuts DOI: http://dx.doi.org/10.5772/intechopen.94189*



#### **Table 2.**

*Chemical formulae of the active principles of* Semecarpus anacardium.

analgesic and anti-inflammatory activity [23]. SA extracts were studied for their antiinflammatory activities *in vitro* using synovial fluid and blood of healthy individuals and rheumatoid arthritis patients. SA inhibited proinflammatory cytokine production like IL-1 beta and IL-12P40 without affecting IL-6 and TNF-alpha production [24].

*Impact of Shodhana on* Semecarpus anacardium *Nuts DOI: http://dx.doi.org/10.5772/intechopen.94189*


**Table 3.**

*Potential uses of* Semecarpus anacardium *with possible mechanism of action.*

#### **4.2 Anticancer activity**

Nut extracts of *Semecarpus anacardium* showed efficacy against human breast cancer cell line (T47D) [25] and mammary carcinoma in rats [26]. It also showed efficacy against leukemic cells in mice [27]. SA extracts have energy restoration, tumor marker regulation and membrane stabilization effect against hepato-cellular carcinoma [28]. *Semecarpus anacardium* may have a protective as well as therapeutic contribution against Mitomycin-C induced mutagenicity [29]. *Semecarpus anacardium* showed significant cytotoxicity having LC50 29.5 μg in brine shrimp lethality test [30]. The mechanism of cytotoxicity is by inducing apoptosis following caspase 3 pathway [31].

#### **4.3 Cardioprotective effect**

*S. anacardium* nuts prevented isoproterenol (ISO) induced myocardial damage in rats [32]. *S. anacardium* (1 mg/100 g body weight) reduced serum cholesterol levels and raised HDL levels in rats fed with atherogenic diet [33]. The process of atherogenesis triggered by lipid peroxidation can be inhibited by *Semecarpus anacardium* [34].

#### **4.4 Nootropic effect**

*Semecarpus anacardium* effectively inhibits acetyl choline esterase which in turn prolongs the half-life of acetylcholine. Hence, SA has been shown to be useful in improving cognitive ability [35–37].

## **4.5 Hepatoprotective effect**

*S. anacardium* decreased the levels of the marker enzymes induced by lead acetate in liver [38]. This hepatoprotective action may be attributed to its anti-oxidant action [39].

### **4.6 Antimicrobial activity**

The flavonoid present in *S. anacardium* showed antifungal activity at 400 mg/ml concentration [40]. Furthermore, the oil possessed anti-microbial activity against both Gram positive (*B. subtilis, S. aureus*) and Gram negative (*P. vulgaris, E. coli*) organisms [41]. The petroleum ether and aqueous extracts of SA inhibit the growth of *Staphylococcus aureus* and *Shigella flexneri*. However, chloroform and ethanol extracts showed inhibition against *Bacillus licheniformis* and *Pseudomonas aeruginosa* respectively [42]. The alcoholic extract of SA was found to be bactericidal against Gram positive (*E. coli*, S. Typhi and *P. vulgaris*) and Gram negative (S aureus and C diphtheria) strains [43]. Water extract showed potential with MIC 6.25 μg/ml against M. tuberculosis during in vitro bioassay [44].

#### **4.7 Aphrodisiac and spermicidal activity**

*Semecarpus anacardium* significantly improved both mounting and mating performance of male mice [45]. However, there are reports of spermicidal activity including spermatogenic arrest in male rats. There is also decrease in density and motility of sperms [36, 46, 47].

#### **4.8 Anthelmintic activity**

Petroleum ether, chloroform extract of nuts of *S. anacardium* showed anthelmintic activities against adult Indian earthworm (Pheretima posthuma) [48].

#### **4.9 Hypoglycemic effect**

Ethanolic extract of SA (100 mg/kg) reduced blood glucose level in normoglycemic rats. However, no effect was observed in case of hyperglycemic rats [49, 50].

#### **5. Toxicity of** *Semecarpus anacardium*

Use of Bhallataka needs adequate precaution due to its extreme hot and sharp attributes. It should be kept away from pregnant women, old aged person and also children. Individual persons showing allergic reactions like rash, itching and swelling to it should avoid its use. Furthermore, it is highly recommended to keep away from direct exposure to sunlight, heat and extreme sex during the course of Bhallataka treatment. The oily portion of nut should be removed for its safe use which can lead to nephropathy. Fewer antidotes like coconut oil, coriander leaves pulp and ghee is useful in case of allergic reactions [51]. The traditional way of administration with peanut oil was proven to be safe up to 25 mg/kg/day for 9 day [52].

Bhallataka nut oil extracts in male albino rats is reported to decrease hemoglobin count as well as erythrocytes indicating anemia. It exhibited an alteration in kidney enzyme level leading to nephrotoxicity during acute and subchronic toxicity [53].

*Impact of Shodhana on* Semecarpus anacardium *Nuts DOI: http://dx.doi.org/10.5772/intechopen.94189*

#### **Figure 3.**

*Flow chart of Shodhana of* Semecarpus anacardium *nuts.*

Hence, it is necessary to undertake Shodhana sanskara of Bhallataka with precaution before using it in medicine to avoid toxic effects of Ashuddha (impure) Bhallataka [54].

#### **6. Shodhana of** *Semecarpus anacardium* **nuts**

The process Shodhana, which is also known as detoxification or purification process signifies the conversion of any poisonous drug into beneficial, non-poisonous/nontoxic drug. *Shodhana* process involves sequential steps to purify and reduce the extreme toxicity levels/principles and also sometimes may result in enhancing the therapeutic efficacy. Shodhana is essential because higher concentrated chemicals may contribute towards adverse episodes on human body. There are 2 types of Shodhana i.e. Samanyashodhana and visheshshodhana which purifies toxic drugs. Furthermore, shodhana limits toxicity by removing the visible and invisible impurities, heterogeneous substances and toxic substances [55].

As per Ayurvedic texts shodhana can be done for SA nuts (**Figure 3**). The thalamus part of the fruit is removed with a steel knife. Then, the nuts are subjected to fresh cow urine daily for 7 days followed by cow milk daily for 7 days followed by rubbing thoroughly with brick powder for 3 days. During the treatment with cow urine and cow milk, the nuts are washed with water before adding fresh cow urine or milk. On the final day (18th day), the nuts are washed with hot water to remove the brick powder. This shodhana procedure is repeated three times [35, 56–58].

### **7. Effect of Shodhana**

Shodhana helps in conversion of toxic urushiol into nontoxic anacardol [56]. Our studies on GC-MS which elucidate the presence of anacardol derivative (Anacardol, tetrahydro-; retention time 51.538 in GC-MS) in shodhit extract and urushiol derivative in pre-shodhit extract (1,2-Benzenediol, 3-(8,11,14-pentadecatrienyl)-, (*Z*,*Z*)-, retention time 56.270 in GC-MS) further confirms that shodhana helps in removal of toxic principle urushiol [59].

Shodhana improves the yield in methanolic extract, but decreases the phenolic and flavonoid content [31]. Shodhana decreases cytotoxicity without affecting anticancer activity significantly. The reduction in cytotoxicity may be attributed to reduction in oxidative stress [59]. Shodhana of the nuts reduce nootropic activity

[35]. So shodhana not only reduces toxicity but also alters its pharmacological activities.

## **8. Conclusion**

*Semecarpus anacardium* is classified in Ayurveda under the category of toxic plants. There are reports of anti-inflammatory activity, anti-arthritic effect, antioxidant activity, antimicrobial activity, anti- carcinogenic activity, hypoglycemic activity, cardioprotective, hepatoprotective, neuroprotective, and hypolipidemic activity etc. shown by *Semecarpus anacardium.* Shodhana of nuts of *Semecarpus anacardium* can be done as per method given in Ayurvedic Pharmacopeia of India. Shodhana improves the yield, decreases the phenolic and flavonoid content; and converts toxic urushiol into nontoxic anacardol derivative thereby reducing toxicity. Shodhana not only reduces toxicity but also alters its pharmacological activities. Shodhana decreases cytotoxicity without affecting anticancer activity significantly. Shodhana also reduces nootropic activity.

## **9. Future scope**

The effect of Shodhana on other pharmacological activities of *Semecarpus anacardium* can be studied in future. This work can also be extended to other poisonous and semi poisonous plants for which shodhana method is described in Ayurvedic Pharmacopeia of India.

## **Acknowledgements**

The authors are grateful to the Siksha O Anusandhan Deemed to be University, Bhubaneswar, India, for providing necessary support and basic infrastructure to make this work successful. The authors also thank Mr. Tapas Ranjan Satapathy for secretarial help.

## **Conflict of interest**

The authors declare that they have no conflict of interest.

## **Abbreviations**


*Impact of Shodhana on* Semecarpus anacardium *Nuts DOI: http://dx.doi.org/10.5772/intechopen.94189*

## **Author details**

Pratap Kumar Sahu<sup>1</sup> \* and Prashant Tiwari<sup>2</sup>

1 School of Pharmaceutical Sciences, Siksha O Anusandhan Deemed to be University, Bhubaneswar-751029, Odisha, India

2 School of Pharmacy, ARKA JAIN University, Jamshedpur-831013, Jharkhand, India

\*Address all correspondence to: pratapsahu@soa.ac.in

© 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.

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**Chapter 18**
