**4. Phytomedicine: promoting synergistic actions in prostate cancer management**

The history of ayurvedic and traditional systems of medicine showed that the medicinal plants have global importance in treating human diseases and disorders [21]. The references of ancient literature, a Sumerian clay slab from Nagpur, approximately 5000 years old suggested that people were depended on drugs from the nature [22]. Theophrast (371-287 BC) in his scientific book titled "De Causis Plantarium" has referred and classified nearly 500 medicinal plants. About 700 plant species including pomegranate, castor oil plant, aloe, senna, garlic, onion, fig, willow, coriander, juniper, common centaury, etc. [23] were reported having medicinal properties. The World Health Organization (WHO) estimated that trades of plantderived pharmaceutical drugs would account for five trillion US dollars by 2050.

The survey reports on these medicinally valued plants and their preparations as tinctures, teas, poultices, powders, and other herbal formulations [24] served as the basis for novel drug discovery wherein a large number of synthetic drugs are developed on the small-molecule natural chemical entities and has been introduced as potential drugs worldwide [25]. Even our natural food intake relays on the medicinal aspects followed in our tradition thus have a strong impact on determining health at different stages/phases of life. In addition many food-based nutrients contribute to the prevention and management of deadly diseases like cancer. Wholesome diet including vegetables, fruit, and vitamins lowers the risk up to 80% of cancers of the large bowel, breast, and prostate.

*Male Reproductive Health*

TNFRs are activated by TNF in order to exhibit cellular response. TNF triggers the transcription of apoptotic proteins through NF-κB thereby achieving cell survival. Activation of TRAFs, such as TRAF2, TRAF5, and TRAF6 results in transduction of cellular response by TNFRs. In TNFRs pathway, TRAF3 acts as a repressor. APRL, BAFF, BAFF-R, BCMA, and TACI belong to the TNF superfamilies and play vital roles in immunity through B cells and T cells. BAFF binds to BAFF-R, BCMA, and TACI, while APRIL bands to two of them—BCMA and TACI only. In this pathway nuclear factors (NF-κB) are activated in signaling cascades. This activation process can be triggered by canonical and non-canonical pathways. The latter is activated by activation of BCMA, TCAI, and BAFF-R by BAFF. This counter activates TRAF2 and TRAF5 that signals NIK, a mitogen activated protein kinase. Once NIK is activated, phosphorylation of IKK-alpha that restrain processing NK-κB2 into NF-κB2 onsets. Along with RelB, NF-κB2 activates Bcl2 or Bcl-XL or both. Upon this activation cell survival is promoted. BAFF transcription is activated by NF-κB2 resulting in a positive feedback. I-kB is phosphorylated by IKK alpha, beta, and gamma which is activated by TRAF2 by canonical pathway. I-kB is disintegrated and ubiquitylated inside proteosome 26S. This process discharges NF-κB2 and RelA which are swiftly repositioned from cytoplasm to nucleus. Following which anti-apoptotic components, such as Bcl-2, Bcl-XL, and BFL1 are activated by transcription by NF-κB transfactors. In non-canonical pathway, IKK alpha is activated by its phosphorylation once NIK kinase is promoted by TRAF. NF-κB2 is processed from p100 to p52 by IKK alpha which is adhered to RelB. The dimer (RelB-p52-NF-κB) engages in affecting gene transcription once it shifts to the nucleus. This pathway does not involve IKK beta and gamma. IKK, RelB, and NIK are mediated by TNF-R1 signal or TNF-R2 signal as well. NF-κB promoted cell growth and proliferation in prostate cancer cells by regulating expression of genes, such as c-myc, cyclin D1, and IL-6. Furthermore, NF-κB-mediated expression of genes involved in angiogenesis (IL-8, VEGF), and invasion and metastasis (MMP 9, uPA, and uPA receptor) may further contribute to

the progression of androgen depleted prostate cancer [20].

E2F in the cytosol, thus blocking the cell cycle at G1 phase.

Apoptosis is programmed cell death involving sequential events of elimination of cells without releasing harmful substances into the surrounding area. Apoptosis plays a crucial role in developing and maintaining the health of the body by eliminating old cells, unnecessary cells, and unhealthy cells. The two classes of regulatory molecules play vital role in the cell cycle progression and apoptosis processes are protein kinases, such as cyclin dependent kinases (CDKs), and cyclins. Disturbances in the cell cycle regulation due to uncontrolled cell growth and divisions through and escaping of the cell cycle checkpoints occur in the mutated cells. The cell cycle events are facilitated through the activated cyclin D-CDK4/6 complexes phosphorylating the retinoblastoma protein (pRb) bound with E2F transcriptional factors. This in turn inactivates pRb and weakening its affinity for E2F which then becomes free to enter the nucleus and transcription of cell cycle progression genes. The hypophosphorylated pRb impounds the transcription factor

Similarly B-cell lymphoma (Bcl-2) family genes are involved in the apoptosis pathway, including prostate, breast, and ovarian cancers. The Bcl-2 family proteins had the anti-apoptotic subgroup, such as, Bcl-extra-large (Bcl-xL), Bcl2-like 2 (Bcl-W), myeloid cell leukemia (Mcl-1) that interacted with another subgroup of proteins called the pro-apoptotic proteins (Bcl2-associated X protein (Bax) and Bcl2 antagonist/killer (Bak)). In the signal transduction cascade of apoptosis the pro-apoptotic proteins began induction of apoptosis *via* mitochondrial outermembrane permeabilization, followed by the release of cytochrome c, and finally the activation of cysteine aspartyl proteases (caspases). Second is the intrinsic pathway, with the release of cyt-c into the cytosol from mitochondria, a multiprotein

**166**

Based on the studies done at the US National Cancer Institute, selenium, vitamin E, and Omega-3 fatty acid have preventive roles in prostate carcinoma [26]. Plants produce a wide range of chemical compounds as by-products of their metabolic pathways known as secondary metabolites. These compounds have no direct role in growth yet they have significant role in defense mechanisms. The secondary metabolites generally flavonoids, tannins, curcumin, resveratrol, and gallocatechin are reported as effective anti-cancer drugs [27]. Molecular studies have proved that luteolin, quercetin, and kaempferol rich in onions, olives, grapes, tea, pomegranate, broccoli, and cauliflower [28] are effective in suppressing tumor development with low dose-limiting toxicities and negligible side effects [29].

Plants in nature contain many active compounds which elicit the synergistic effects in combination with chemical drugs through its own molecular mechanisms of targeting signaling pathways in cancer cells in order to overcome drug resistant cancers, also strengthens the therapeutic activity of chemical drugs and subsides drug-induced toxicity. The pharmacological efficacies of chemotherapeutic drugs are improvised by alteration in the pharmacokinetics of drug compounds regulating the receptor targets and downstream effector molecules in the cancer cells.

Sporadically, anti-androgens (anti-hormones) are administered for initial stages of prostate cancer which is prone to frequent failures in patients diagnosed with recurrent androgen-independent prostate cancer and metastasis. Radiotherapy and/or androgen deprivation therapy can be considered as an adjunct to surgery, in either the adjuvant or salvage setting, to further control the disease course. These combinatorial therapies are highly recommended in combating primary tumors, but metastatic tumors are more challenging due to loss of remedial activity and disease remission. Also these therapies are reported in exerting complications of damaging the normal cells in vicinity of tumor growth, disturbing the functioning of immune system, triggering autoimmunity [30], damage to adjacent gastrointestinal tract, and bladder incontinence. Hence, multifaceted therapies producing synergistic effects and long-term outcomes by lowering the local tumor burden and eradicating metastatic disease compared to each individual change are required for cancer management.

Prostate cancer is characterized by slow growth and long latency period and thus integration of phytochemicals/compounds in combination with other existing therapies have promising future to manage cancer, controlling the disease progression and mortality rate. The WHO has estimated that approximately 80% of the world's population depends on traditional plant-based medicines for meeting their primary health care needs [31]. In prostate cancer, there is an imbalance between prostate cell growth and apoptosis. In prostate cancer these proteins are over expressed which lead to progression of metastatic prostate cancer through inhibition of apoptotic cell death. This over expression also causes resistance to heat-shock stress, several chemotherapies, and radiotherapy. Phytochemicals are routinely used as an adjuvant to conventional chemo and radio therapies of cancer in order to manage the drug-resistance mechanisms and resensitize tumor cells.

Many medicinal plants are reported to possess chemopreventive activities on prostate cancer exhibiting significant oestrogenic and anti-androgen effects, such as *Agathosma betulina* [32], *Bidens pilosa* [33], *Prunus Africana*, *Cucurbita pepo L*. [34], *Andrographis paniculata* [35], *Vaccinium macrocarpon* [36], *Linum persicum* and *Euphorbia cheradania* [37], *Panax ginseng* [38], *Scutellaria baicalensis* [39], *Wedelia chinensis* [40], *Urtica membranaceae*, *Artemisia monosperma* and *Origanum dayi* [41], *Vitis vinifera* [42], an eight-herb Chinese formulation, that consists of *Isatis indigotica*, *Glycyrrhiza glabra*, *Glycyrrhiza uralensis*, *Scutellaria baicalensis*, *Ganoderma lucidum*, *Panax ginseng*, *Dendranthema morifolium*, *Rabdosia rubescens* [43]. Combined drugs made of vinca alkaloids, Taxus diterpenes, Podophyllum

**169**

**5. Conclusion**

peutic drugs in cancer management.

*Combinatorial Drug Therapy with Phytochemicals as Adjuvants in Prostate Cancer Management*

Quercetin and curcumin, plant-derived flavanoids are well established drugs in cancer treatment exhibiting antioxidant, anti-inflammatory, and anti-proliferative activities [51]. Quercetin has anti-inflammatory role through regulation of NF-κB pathway genes [52] inhibiting the expression of pro-inflammatory cytokines, TNF-α, IL-6, and IL-1β and inflammatory mediators, nitric oxide, and catalase. Combination of quercetin with doxorubicin increases the sensitivity of PC3 resistant cells by inducing apoptosis *via* reduction of mitochondrial membrane potential, activation of the PI3K/AKT pathway, and acceleration of chemo resistance [53]. The chemopreventive and anti-neoplastic activity of the phytochemicals could be achieved through multiple effects including reduction of PSA and AR expression, induction of apoptotic pathways, inhibition of angiogenesis, induction of PKC-α, suppression of TrkE, induction of p53, inhibition of proteasome activity, induction of S-phase and G0/G1 phase and G2/M cell-cycle arrest, suppression of DNA synthesis, up-regulation of protein expression WAF1/p21, KIP1/p27, INK4a/ p16, INK4c/p18, down-regulation of protein expression cyclin D1 and D3, cyclin E, cdk2, cdk4, cdk6, inhibition of PI3K/PKB phosphorylation of AKT, Inhibition of COX-2 expression [54]. *Wedelia chinensis* extract possesses the ability in reducing the gene expressions of proinflammatory cytokines and STAT3 activity in tumorelicited myeloid cells [40]. Altogether, the combination of herbal compounds includes pharmacokinetic and pharmacodynamic synergisms to provide significant therapeutic effects. Baicalein form *Scutellaria baicalensis* [39] reduces the synthesis of eicosanoid that function as important mediators in inflammatory responses

lignans, and Camptotheca alkaloids were proved with anticancer effects [44]. Pentacyclic triterpenoids reported in *Hypoxis hemerocallidea* reduced the inflammation and swelling in the prostate. Garlic and green tea catechins act as potential chemopreventive agents against cancer by inhibiting PIN [45]. Phytochemicals like geneistin and quercitin [46], lycopene [47], curcumin, epigallocatechin-gallate, resveratrol [48], brassinosteroid [49], derived from medicinal plants have been reported through *in-vitro* studies with potentials of anti-proliferative effects on prostate cancer cell lines, such as PC-3, DU-145, and LNCaP. Their protective action against cancer may be due to their high concentration of antioxidants that react

*DOI: http://dx.doi.org/10.5772/intechopen.86157*

with free radicals thereby neutralizing them [50].

through inhibiting enzymatic oxidation of essential fatty acids.

promoter of PSA, decline of PSA levels proves down-regulation of AR [57].

Thus multimodal approach of treating prostate cancer with the integration of phytochemicals as chemopreventive agents in down-regulation of cell proliferation and induction of apoptosis has taken forefront in development of potential thera-

One of our studies reported that, a potential medicinal herb *Gymnema sylvestre* has been proved for its potency to control prostate cancer progression [55]. It is (family: Asclepiadaceae) described as miracle fruit, is native to central and western India that has been used in the traditional health care system, for several centuries [56]. The leaves are rich in triterpene classes of oleanane saponins (gymnemic acids and gymnemasaponins) and dammarene saponins (gymnemasides). The phytocompound dihydroxy gymnemic triacetate (DGT) isolated from acetone extract of *G. sylvestre* leaves were effective in inhibiting prostate cancer cell growth, inducing apoptosis, modulation of cell cycle, and downregulation of the protein expressions. Also the depletion of PSA observed in the PC-3 cell line caused by DGT was observed. Since PSA gene is positively regulated *via* binding of AR to the androgen responsive elements in the

*Combinatorial Drug Therapy with Phytochemicals as Adjuvants in Prostate Cancer Management DOI: http://dx.doi.org/10.5772/intechopen.86157*

lignans, and Camptotheca alkaloids were proved with anticancer effects [44]. Pentacyclic triterpenoids reported in *Hypoxis hemerocallidea* reduced the inflammation and swelling in the prostate. Garlic and green tea catechins act as potential chemopreventive agents against cancer by inhibiting PIN [45]. Phytochemicals like geneistin and quercitin [46], lycopene [47], curcumin, epigallocatechin-gallate, resveratrol [48], brassinosteroid [49], derived from medicinal plants have been reported through *in-vitro* studies with potentials of anti-proliferative effects on prostate cancer cell lines, such as PC-3, DU-145, and LNCaP. Their protective action against cancer may be due to their high concentration of antioxidants that react with free radicals thereby neutralizing them [50].

Quercetin and curcumin, plant-derived flavanoids are well established drugs in cancer treatment exhibiting antioxidant, anti-inflammatory, and anti-proliferative activities [51]. Quercetin has anti-inflammatory role through regulation of NF-κB pathway genes [52] inhibiting the expression of pro-inflammatory cytokines, TNF-α, IL-6, and IL-1β and inflammatory mediators, nitric oxide, and catalase. Combination of quercetin with doxorubicin increases the sensitivity of PC3 resistant cells by inducing apoptosis *via* reduction of mitochondrial membrane potential, activation of the PI3K/AKT pathway, and acceleration of chemo resistance [53]. The chemopreventive and anti-neoplastic activity of the phytochemicals could be achieved through multiple effects including reduction of PSA and AR expression, induction of apoptotic pathways, inhibition of angiogenesis, induction of PKC-α, suppression of TrkE, induction of p53, inhibition of proteasome activity, induction of S-phase and G0/G1 phase and G2/M cell-cycle arrest, suppression of DNA synthesis, up-regulation of protein expression WAF1/p21, KIP1/p27, INK4a/ p16, INK4c/p18, down-regulation of protein expression cyclin D1 and D3, cyclin E, cdk2, cdk4, cdk6, inhibition of PI3K/PKB phosphorylation of AKT, Inhibition of COX-2 expression [54]. *Wedelia chinensis* extract possesses the ability in reducing the gene expressions of proinflammatory cytokines and STAT3 activity in tumorelicited myeloid cells [40]. Altogether, the combination of herbal compounds includes pharmacokinetic and pharmacodynamic synergisms to provide significant therapeutic effects. Baicalein form *Scutellaria baicalensis* [39] reduces the synthesis of eicosanoid that function as important mediators in inflammatory responses through inhibiting enzymatic oxidation of essential fatty acids.

One of our studies reported that, a potential medicinal herb *Gymnema sylvestre* has been proved for its potency to control prostate cancer progression [55]. It is (family: Asclepiadaceae) described as miracle fruit, is native to central and western India that has been used in the traditional health care system, for several centuries [56]. The leaves are rich in triterpene classes of oleanane saponins (gymnemic acids and gymnemasaponins) and dammarene saponins (gymnemasides). The phytocompound dihydroxy gymnemic triacetate (DGT) isolated from acetone extract of *G. sylvestre* leaves were effective in inhibiting prostate cancer cell growth, inducing apoptosis, modulation of cell cycle, and downregulation of the protein expressions. Also the depletion of PSA observed in the PC-3 cell line caused by DGT was observed. Since PSA gene is positively regulated *via* binding of AR to the androgen responsive elements in the promoter of PSA, decline of PSA levels proves down-regulation of AR [57].

### **5. Conclusion**

Thus multimodal approach of treating prostate cancer with the integration of phytochemicals as chemopreventive agents in down-regulation of cell proliferation and induction of apoptosis has taken forefront in development of potential therapeutic drugs in cancer management.

*Male Reproductive Health*

cancer management.

Based on the studies done at the US National Cancer Institute, selenium, vitamin E, and Omega-3 fatty acid have preventive roles in prostate carcinoma [26]. Plants produce a wide range of chemical compounds as by-products of their metabolic pathways known as secondary metabolites. These compounds have no direct role in growth yet they have significant role in defense mechanisms. The secondary metabolites generally flavonoids, tannins, curcumin, resveratrol, and gallocatechin are reported as effective anti-cancer drugs [27]. Molecular studies have proved that luteolin, quercetin, and kaempferol rich in onions, olives, grapes, tea, pomegranate, broccoli, and cauliflower [28] are effective in suppressing tumor development with

Plants in nature contain many active compounds which elicit the synergistic effects in combination with chemical drugs through its own molecular mechanisms of targeting signaling pathways in cancer cells in order to overcome drug resistant cancers, also strengthens the therapeutic activity of chemical drugs and subsides drug-induced toxicity. The pharmacological efficacies of chemotherapeutic drugs are improvised by alteration in the pharmacokinetics of drug compounds regulating

Sporadically, anti-androgens (anti-hormones) are administered for initial stages of prostate cancer which is prone to frequent failures in patients diagnosed with recurrent androgen-independent prostate cancer and metastasis. Radiotherapy and/or androgen deprivation therapy can be considered as an adjunct to surgery, in either the adjuvant or salvage setting, to further control the disease course. These combinatorial therapies are highly recommended in combating primary tumors, but metastatic tumors are more challenging due to loss of remedial activity and disease remission. Also these therapies are reported in exerting complications of damaging the normal cells in vicinity of tumor growth, disturbing the functioning of immune system, triggering autoimmunity [30], damage to adjacent gastrointestinal tract, and bladder incontinence. Hence, multifaceted therapies producing synergistic effects and long-term outcomes by lowering the local tumor burden and eradicating metastatic disease compared to each individual change are required for

Prostate cancer is characterized by slow growth and long latency period and thus integration of phytochemicals/compounds in combination with other existing therapies have promising future to manage cancer, controlling the disease progression and mortality rate. The WHO has estimated that approximately 80% of the world's population depends on traditional plant-based medicines for meeting their primary health care needs [31]. In prostate cancer, there is an imbalance between prostate cell growth and apoptosis. In prostate cancer these proteins are over expressed which lead to progression of metastatic prostate cancer through inhibition of apoptotic cell death. This over expression also causes resistance to heat-shock stress, several chemotherapies, and radiotherapy. Phytochemicals are routinely used as an adjuvant to conventional chemo and radio therapies of cancer in order to manage the drug-resistance mechanisms and resensitize tumor cells. Many medicinal plants are reported to possess chemopreventive activities on prostate cancer exhibiting significant oestrogenic and anti-androgen effects, such as *Agathosma betulina* [32], *Bidens pilosa* [33], *Prunus Africana*, *Cucurbita pepo L*. [34], *Andrographis paniculata* [35], *Vaccinium macrocarpon* [36], *Linum persicum* and *Euphorbia cheradania* [37], *Panax ginseng* [38], *Scutellaria baicalensis* [39], *Wedelia chinensis* [40], *Urtica membranaceae*, *Artemisia monosperma* and *Origanum dayi* [41], *Vitis vinifera* [42], an eight-herb Chinese formulation, that consists of *Isatis indigotica*, *Glycyrrhiza glabra*, *Glycyrrhiza uralensis*, *Scutellaria baicalensis*, *Ganoderma lucidum*, *Panax ginseng*, *Dendranthema morifolium*, *Rabdosia rubescens* [43]. Combined drugs made of vinca alkaloids, Taxus diterpenes, Podophyllum

the receptor targets and downstream effector molecules in the cancer cells.

low dose-limiting toxicities and negligible side effects [29].

**168**

*Male Reproductive Health*
