**3. Molecular regulations in prostate cancer**

The inappropriate expression of the growth inhibitory factors appears to contribute to prostate cancer progression. Epidermal growth factor (EGF) promotes chemo-migration of metastatic prostate cancer cells to lymph node and medullary bone sites [18]. In insulin signaling pathway, the ligand insulin binds to its receptor followed by tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase. Several studies suggested that alteration in the IGF signaling axis is associated with an increased risk of prostate cancer [19]. Signal transduction proteins interact with IRS including GRB2. GRB2 is a part of the cascade including SOS, RAS, RAF, and MEK that leads to activation of MAPK and mitogenic response in the form of gene transcription.

In AKT signaling pathway, PTEN is a regulator which is down regulated to protect the cell from tumor growth. The phosphatase activity on phosphatidylinositol 3,4,5-triphosphate allows dephosphorylation of PIP3 to PIP2. The PIP2 inhibits the P13K which is the membrane bound domain. When the phosphatase activity is lost, P13K transfers its phosphate group to PDK1 and PDK2 which in turn causes phosphorylation of AKT protein and regulatory amino acids Ser473 and Thr308. This leads to activation of MDM2, P21, CASP9, mTOR genes leading to apoptosis inhibition, tumor growth, etc. Smad3 gene plays a key role in prostate cancer serving as an essential mediator of most Smad-dependent TGF-beta responses, including control of gene expression, cell growth, apoptosis, and tumor suppression. Deregulated/ enhanced expression and activation of AR in prostate carcinomas may intercept the tumor suppressor function of TGF-β through transcriptional suppression of Smad3.

*Male Reproductive Health*

tufting, micropapillary, cribriform, and flat [5].

istered based on the stage of cancer progression.

**2. Androgen-dependent and androgen-independent prostate cancer**

receptor (AR), a nuclear transcription factor that controls expression of genes

involved in growth, differentiation, homeostatsis, and apoptosis. Receptor for steroid and thyroid hormones are mostly cytoplasmic/nuclear receptors and hormonereceptor complex binding to the promoter regions of responsive genes and stimulate or inhibit transcription from those genes. Nuclear receptors are ligand-inducible transcription factors that mediate the signals of a broad variety of fat-soluble hormones, including the steroid and vitamin D3 hormones, thyroid hormones retinoids.

Human prostate is a walnut shaped, fibromuscular organ located beneath the urinary bladder and is made-up of several glandular and non-glandular components that are tightly fused together within a common capsule [9]. It is an exocrine gland functioning in secretion of complex proteolytic solution into the urethra during ejaculation which is important for sperm motility and nourishment. The growth and function of the prostate are regulated by androgens. The growth and development of normal prostate requires functioning androgen signaling pathway, which is regulated by hypothalamic-pituitary gonadal axis. Androgens (includes testosterone and DHT) are responsible for the male secondary sexual characteristics. Testosterone is synthesized in the testes and released into the circulation in response to specific hormonal signals regulated by GnRH, FSH, and LH. Testosterone is transported by steroid hormone binding globulin (SHBG) to the prostate, where it is converted by 5α-reductase to its active metabolite 5α-dihydrotestosterone (DHT). In the prostate, androgens mediate their effects *via* high affinity to the androgen

and veins causing lower body edema. The development of high-grade prostatic intraepithelial neoplasia (HGPIN) is identified as an intermediate stage between benign epithelium and the invasive malignant carcinoma at the outset of prostate cancer. Four main patterns of high-grade PIN (HGPIN) have been described as

Prostate specific antigen (PSA), major constituent in prostatic secretion and is used for screening prostatism. PSA testing is primarily associated with benign prostatic hyperplasia (BPH), however there is only rare connectivity of patients having BPH to develop prostate cancer. With conditions like BPH, inflammation, and disruption of prostate basal membrane increases the permeability and releases PSA into the circulation. Prostate cancer antigen 3 (PCA3) is more specific than PSA which is an important biomarker in personalized medicine. Also analysis of urinary protein markers, such as TMPRSS2-ERG and PCA3 are helpful in early diagnosis of the disease. The other tumors markers reported as prostatic acid phosphatase (PAP), cytoskeletal proteins, and annexin I are downregulated in PIN whereas C-erbB-2 (HER-2/neu) and C-erbB-3 oncoproteins, c-met protooncogene, Bcl-2 oncoprotein, several growth factors, nitric oxide synthase, alpha-methylacyl-CoA racemase, glycoprotein A-80, and apolipoprotein D, are upregulated in PIN. The histological grading system of prostate cancer is obtained from the Gleason score [6] which provides information that score 1–5 indicates low-grade prostate cancer and score 8–10 indicates high-grade prostate cancer. Digital rectal examination (DRE), examination of PSA levels, prostate ultrasound, and prostate biopsy are the current diagnostic methods in examining the primary and metastatic stages for prostate cancer [7, 8]. Prostate cancer stages are generally classified into three categories—T category, N category, and M category. T represents the primary tumor, N represents the cancer that has spread to regional (nearby) lymph nodes and M represents the distant metastasis cancer. The treatment strategies are admin-

**164**

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].

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

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

**167**

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

caspase-activating complex, called "apoptosome" binds procaspase-9 and cyt-c with its central component Apaf1, and activates apoptosis. Thus there should be a balance in the levels of anti-apoptotic and pro-apoptotic proteins for the proper

*Molecular pathways involved in prostate cancer progression (developed by pathway construction tool—PathVisio).*

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

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%

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

progression of apoptosis (**Figure 1**).

of cancers of the large bowel, breast, and prostate.

**management**

**Figure 1.**

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

**Figure 1.** *Molecular pathways involved in prostate cancer progression (developed by pathway construction tool—PathVisio).*

caspase-activating complex, called "apoptosome" binds procaspase-9 and cyt-c with its central component Apaf1, and activates apoptosis. Thus there should be a balance in the levels of anti-apoptotic and pro-apoptotic proteins for the proper progression of apoptosis (**Figure 1**).
