review literature - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/62177/2...aromatase...

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REVIEW & LITERATURE

VIKAS VERMA Review of Literature

Investigation of novel synthetic molecules and natural products for prostatic hyperplasia 5

2.1 Prostate

The prostate is a fibro muscular exocrine gland of the male accessory reproductive

system which expels a complex proteolytic solution into the urethra during

ejaculation(Corradi et al., 2013; Ismail et al., 2013).The proteolytic enzymes liquefy

the semen after ejaculation and the phosphatases and salts change the vaginal

environment to enhance sperm survival.

In men, the gland surrounds the first 3 cm of the urethra (prostatic urethra) as it leaves

the urinary bladder. The ejaculatory ducts enter dorsally and join the urethra within the

gland on either side of the prostatic utricle(Kumar and Majumder, 1995). Anatomically,

the most caudal aspect of the gland, which opposes the urinary bladder is termed the

base of the gland. The walls of the prostatic urethra are highly convoluted and lined

with transitional epithelium. In its resting (not distended) state, the ureter has a

longitudinal ridge (the urethral crest) running the length of the gland. The majority of

the ductal glands secrete into longitudinal grooves (the urethral sinuses) formed on

either side of the ridge. Near the junction of the ejaculatory tubes and the urethra is a

short diverticulum in the urethral crest. This is the prostatic utricle, the male vestigial

remnants of the female uterus and vagina.["Prostate Gland Development". ana.ed.ac.uk.

Archived from the original on 2003-04-30. Retrieved 2011-08-03]

Fig. 2.1.1. The overview of Prostate. A represents the cross-sectional view of lower

abdomen showing prostate gland. B represents the HE staining of prostate showing

structural architecture of prostate (Figure source :

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http://web.archive.org/web/20030430000050/http://www.ana.ed.ac.uk/database/p

rosbase/prosdev. html)

The prostate is covered by a thin vascularized fibrous sheath which surrounds a fibro

muscular layer continuous with the smooth muscle surrounding the bladder (Corradi et

al., 2013). The fibro muscular layer extends within the organ as septae, dividing the

gland into ill-defined lobules and functional areas.

The secretory components of the gland are divided into three concentric

layers(Ramirez-Balderrama et al., 2013). The innermost area is comprised of mucosal

glands which are concentrated around and secrete into the upper region of the prostatic

urethra(McNeal, 1968).The middle or internal area contains sub mucosal glands which

secrete via short ducts into the urethral sinuses. The outer or peripheral area constitutes

the majority of the gland and secretes via long ducts into the urethral sinuses. The

anterior isthmus is an area of the gland ventral to the urethra, relatively free of glands

and rich in fibro muscular tissue(McNeal, 1968).

The prostate is a compound tubuloacinar gland. Within the acini and tubules, the

epithelium forms complex folds and papillae supported by a thin highly vascularized

loose connective tissue(Shidaifat et al., 2007). The fluid secreted by the prostate gland

is rich in acid phosphatase and citric acid(Chow et al., 1993). It contains the proteases

fibrinolysin and prostate specific antigen (PSA), the enzyme amylase, kallikreins,

semenogelin, fibronectin, phospholipids, cholesterol, zinc, calcium and many proteins

of unknown functions such as the beta-microseminoprotein (Selvakumar et al., 2011;

Hu and Zhao, 2013; Flatley et al., 2014; Hong, 2014).

2.2 Benign Prostatic Hyperplasia

Benign prostatic hyperplasia (BPH) is a highly prevalent disorder that affects more than

50% of men older than 50 years with increasing incidence rates in proceeding age. The

prostate gets larger in most men as they get older, and, majority of men over the age of

50 years can expect to suffer from the symptoms of BPH if they survive for another 30

years. (Verhamme et al., 2002). Histologically distinguishable BPH is present in about

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8% of men aged 31 to 40 years, and this prevalence increases markedly with age to

about 90% by the ninth decade of life, establishing BPH as a chronic disease that spans

over decades (Rosen et al., 2003; Rosen et al., 2005). BPH is associated with

obstructive and irritative lower urinary tract symptoms (LUTS), which may have a

negative impact on patient’s quality of life. Lower urinary tract symptoms include

urgency, frequency, nocturia, hesitancy, intermittency, weak urine stream and

incomplete emptying. More serious complications of BPH include acute urinary

retention (AUR), renal insufficiency, urinary tract infection, gross hematuria, bladder

stones, and renal failure. Lack of or inadequate management of BPH may precipitate or

worsen these conditions.

2.2.1 Etiology of BPH

Although the etiology of BPH has not been clearly defined, the disorder most likely

involves age-related proliferation of stromal and glandular cells in the periurethral and

transition zones of the prostate gland due to long-term exposure of prostatic tissue to

steroid hormones. The microscopic proliferative process that occurs in prostatic tissue

may eventually result in an enlarged prostate, which may constrict the urethra and lead

to bladder outlet obstruction. In addition, this process increases the smooth muscle tone

of the prostate, which is also associated with urethral constriction and is mediated by

α-1-adrenergic receptors (Fine and Ginsberg, 2008). Since prostate surgery and AUR

cause significant pain, discomfort, economic and emotional burden, it is important to

consider therapeutic approaches that reduce the risk of such progression events while

also achieving symptomatic relief.

Over the last decade, there has been a considerable decline in the popularity of surgery

to manage symptoms associated with BPH, and medical therapy is now the most

frequently used treatment option in clinical practice. Hence, patients with mild or

moderate symptoms can normally be treated in a primary care setting, while more

complicated cases may be referred to an urologist for evaluation and management.



Treatment of LUTS with plant extracts (phytotherapies) has a long tradition in countries

such as France and Germany, and is also popular in other parts of the world

(Madersbacher et al., 2004). However, their mode of action is unclear and the clinical

efficacy of these agents is largely unproven (Meyer et al., 2001). Additional well-

designed clinical studies are therefore needed before plant extracts can be

recommended for the treatment of LUTS. Current guidelines focus on alpha-blockers

and 5-alpha-reductase inhibitors (5ARIs), as mono-therapies or in combination, when

recommending medical therapy for BPH (Fine and Ginsberg, 2008).

For men with mild to moderate urinary symptoms without much trouble, watchful

waiting and life-style changes are recommended as the side effects of medical therapy

outweigh potential benefits in quality of life. If urinary symptoms worsen, medical

therapy with α-adrenergic blockers alone, or in combination with 5-α-reductase

inhibitors (for men with larger prostates), are recommended. Minimally invasive

therapies (e.g. microwave therapy, transurethral needle ablation) to invasive surgeries

(transurethral resection or TURP, laser ablation or open prostatectomy) are ultimate

options. However, more aggressive treatment approaches harbor greater potential for

associated morbidities and therefore the potential risks and benefits are to be accurately

evaluated. The current international standard for measuring the severity of BPH is the

International Prostate Symptom Score (IPSS) for disease specific quality of life

question. This evaluation consists of seven questions, each scored from 0 to 5 (0–35)

in an increasing order of symptom severity (e.g. urinary frequency, nocturia, bladder

emptying) for deciding the management protocol (Skolarus and Wei, 2009).

2.2.2 Role of estrogens in development of BPH

Interestingly estrogens are capable of stimulating as well as inhibiting growth in

prostate. This duality of action is due to the two subtypes of estrogen receptor: ER-α

and ER-β. Estrogen action via the ER-α causes aberrant cellular differentiation and

proliferation with progression to prostatic hyperplasia, neoplasia and dysplasia. ER-α

is primarily localized in stromal tissue and has been implicated in stromal cell

hyperplasia and the development of the stromal adenoma that causes bladder outflow



obstruction associated with BPH. Estrogens may also exert a synergistic role with di-

hydro testosterone (DHT) in promoting this effect, especially in suppression of

apoptosis. Estrogen accumulation in the human prostate is an age-dependent event

(Krieg et al., 1993a). Concentrations of estradiol-17ß and estrone increase in the stroma

with increasing age while that in epithelial tissue remain constant. Interestingly, DHT

concentrations in the epithelium decrease with increasing age, whereas the levels in

stroma remain fairly constant. There is an overall enhanced estrogenic influence,

relative to that of DHT, in the elderly man. Age-related decrease in DHT levels of the

transition zone (the site of BPH development) of the human prostate and enhanced

estrogen/androgen ratio in this region is clearly implicated (Shibata et al., 2000).

Figure 2.2.1 showing normal prostate and its enlargement in hyperplasic condition

(BPH).

The synergistic action of androgens and estrogens in promoting smooth muscle

hyperplasia seems fundamental to the complex epithelial-stromal interactions (Walsh

and Wilson, 1976). Recently, an antiproliferative action of estrogen mediated by

epithelial ER-β has been suggested (Weihua et al., 2001; Weihua et al., 2002; Imamov

et al., 2004b). Prostatic hyperplasia which develops in estrogen deficient aromatase

knock-out (ArKO) mouse is ablated following the administration of an ER-β-specific

(but not ER-α) agonist.



Figure 2.2.2 Representing the function of estrogens and androgens and their

corresponding receptors during prostate development and homeostasis.

Testosterone is converted to estradiol by the enzyme aromatase. Estradiol in turn, binds

to estrogen receptor α or β in the prostate. Testosterone is also converted to the more

potent dihydrotestosterone (DHT) by the enzyme 5α-reductase in reproductive tissues.

DHT activates the androgen receptor (AR) and is also converted to 3β-androstanediol

by 17β hydroxysteroid dehydrogenase (17βHSD6). In terms of proliferation, there is a

combined stimulatory role of estrogen receptor α and androgen receptors in the prostate

whereas estrogen receptor β inhibits proliferation and stimulates differentiation.

Aromatase required for aromatization of testosterone to estradiol activates both ER-α

and ER-β. In the absence of ERβ signaling, in aromatase knockout (ARKO) mice

(similar to aromatase inhibitor treated men), increased cell proliferation results in

epithelial hyperplasia (Weihua et al., 2002). Therefore, estrogens, acting in synergy

with androgens and ER-β, are required to regulate the proliferative and antiproliferative

changes that occur during normal prostate development and differentiation(Tang and

Yang, 2009).

2.2.3 Epithelial stromal interactions in BPH

Stromal-epithelial interactions play critical roles in the hormonal, cellular, and

molecular regulation of normal prostate as well as in the pathogenesis of prostatic



hyperplasia (Cunha et al., 2004b). Gradual accumulation of prostatic mass as a result

of continuing glandular stromal interactions supplemented by enhanced stimulation by

growth factors result in urinary symptoms in aged men. Stromal cells have been shown

to modulate the prostatic epithelium (Cunha et al., 1983). Increased expression of

peptide growth factors or their receptors also contribute significantly in the

development of BPH. The stromal cells secrete fibroblast growth factors, insulin-like

growth factors I and II, as well as transforming growth factors, which stimulate growth

in stroma itself by autocrine interactions, and also proliferate the epithelium by

paracrine mechanisms (Tang and Yang, 2009). Epidermal growth factor (EGF) system

stimulation induces proliferation of epithelial cells derived from the prostate through

stroma-epithelium interactions (Sorensen et al., 2000).

2.2.4 Angiogenesis and BPH

The prostatic vascular system plays an important role in controlling prostatic size. A

dramatic reduction of blood flow is an early post castration change in prostatic tissue,

which is dependent on androgen. The rapid degeneration of the prostate gland blood

capillaries is related to a complex change in vascular regulatory factors expressed by

the prostate after castration (Naughton et al., 2001). Loss of prostate cells by apoptosis

may be driven by hypoxia and/or scarce nutrition that follow reduced blood flow in the

prostate. Conversely, the abnormal prostate growth process associated with human

BPH is accompanied by an angiogenic process providing sufficient nutrition and

oxygenation for survival of growing mass of prostate cells. Hence prostatic vascular

system has been considered a target for the development of designed therapies for BPH.

Finasteride has been shown to suppress blood flow and vascular development in human

BPH (Memis et al., 2008). Being associated with increased age as in BPH,

cardiovascular disease is now being recognized as an important risk factor for prostatic

hyperplasia (Weisman et al., 2000). Likewise, spontaneously hypertensive laboratory

rats also appear to develop a condition similar to BPH (Golomb et al., 2000), which

intensifies with age. Correspondingly phenylephrine, an α-adrenergic agonist that

induces hypertension, also induces atypical glandular BPH in treated rats(Golomb et

al., 1998).



2.2.5 Altered gene expression in BPH

The gene expression patterns in BPH are different from normal and cancer prostates.

Genes which are consistently upregulated in BPH in comparison to normal prostatic

tissues include growth factors and their receptor proteins (e.g. IGF-I and -II, TGF-beta,

BMP5, latent TGF-beta binding protein 1 and -2); hydrolases, proteases, and protease

inhibitors (e.g., neuropathy target esterase, MMP2, alpha-2-macroglobulin); stress

response enzymes (e.g., COX2, GSTM5); and extracellular matrix molecules (e.g.,

laminin alpha 4 and beta 1, chondroitin sulfate proteoglycan 2, lumican). Conversely,

some genes are consistently suppressed in BPH than in normal prostate tissues and

include the transcription factor KLF4, thrombospondin 4, nitric oxide synthase 2A,

transglutaminase 3, and gastrin releasing peptide(Luo et al., 2002; Tang and Yang,

2009). Several genes associated with cell proliferation like calcium/calmodulin-

dependent serine kinase, phosphoserine phosphatase, S-phase kinase-associated protein

2 or p45 are significantly up-regulated in symptomatic BPH, while genes (including

oncogenes) like ras-related protein, v-jun, v-fos etc are highly up-regulated in BPH with

cancer (Tang and Yang, 2009). Several inflammatory mediator genes like lymphotoxin

beta, immunoglobulins, and chemokine receptors, cytokines, including RANTES,

osteonectin, lumican distinguish symptomatic BPH from BPH with cancer(Olson et al.,

2010).

2.2.6 Medical Management for BPH

The two primary medications for BPH management are:-

1. Alpha blockers: - Alpha blockers (technically α1-adrenergic receptor

antagonists) are the most common choice for initial therapy (Black et al., 2006;

Roehrborn et al., 2007)and are drugs of choice for quick symptomatic relief.

Alpha blockers relax smooth muscles in the prostate and the bladder neck, thus

decreasing the blockage of urine flow. Alpha blockers used for BPH include

doxazosin, (MacDonald et al., 2004) terazosin, alfuzosin, (Roehrborn, 2001;

MacDonald and Wilt, 2005) tamsulosin, and silodosin. All five are equally

effective but have slightly different side effect profiles (Djavan and Marberger,

1999). Terazosin is the most extensively investigated α1-blocker



(Elhilali et al., 1996) and doxazosin is a long–acting α1-blocker that has been

investigated in BPH(Kurth, 1995). Common side effects of alpha blockers

include orthostatic hypotension, ejaculation changes, nasal congestion, and

weakness. Non-selective alpha blockers such as Terazosin and Doxazosin may

also require titration as they can cause syncope if the dose is too high. Side

effects can also include erectile dysfunction.

5α-reductase inhibitors: - Another treatment option is the 5α-reductase inhibitors

finasteride (Gormley et al., 1992) and dutasteride (Roehrborn et al., 2002). These

medications inhibit 5 α -reductase, which in turn inhibits the production of DHT, a

hormone responsible for prostatic growth. There are currently two 5 ARIs licensed

for the management of BPH, finasteride and dutasteride. Dutasteride, the only 5

ARI to inhibit both type 1 and type II 5-α reductases, induces a more profound

reduction of serum DHT in the range of 90–95% compared with 70–75% for

finasteride. Side effects include decreased libido and ejaculatory or erectile

dysfunction.

Table. 2.2.1 Pharmaceutical drugs currently used for the management of

BPH(McGinnis, 1990)

DrugClass Mechanisms Primaryeffects Examples Sideeffects

α-

adrenergic

receptor

blocker

Antagonises the

α-adrenergic

receptors that

contracts the

smooth muscles

in the prostate

and bladder.

Relaxation of

the bladder and

prostate

muscles, thus

relieving the

symptoms of

BPH (difficulty

in urination).

Terazosin,

Doxazosin,

Alfuzosin

Decreased sexual

ability, back pain,

headache, fatigue,

weight gain, blurred

vision, oedema, rhinitis,

orthostatic hypotension,

upper respiratory tract

infection

α1A-

adrenergic

receptor

blocker

Selective for

α1A-adrenergic

receptor which

are the dominant

α-adrenoceptors

in the prostate.

More specific

for symptomatic

treatment of

BPH.

Tamsulosin Ejaculatory disorders,

back pain, chest pain,

sinus problems,

diarrhea, sleepiness

http://en.wikipedia.org/wiki/Terazosin

http://en.wikipedia.org/wiki/Doxazosin

http://en.wikipedia.org/wiki/Titration_(disambiguation)

http://en.wikipedia.org/wiki/Syncope_(medicine)

http://en.wikipedia.org/wiki/Libido



5α-reductase

TypeII

inhibitor

Specifically

inhibits the

conversion of

testosterone into

DHT by5α-

reductase TypeII,

the main isoform

in the prostate.

Checks the

growth of the

prostate.

Finasteride Impotence,

hypersensitivity

(allergy to active

ingredients),

rash(allergic reaction),

Breast

tenderness/swelling,

ejaculatory disorders,

decreased sex drive

5α-reductase

Type I& II

inhibitor

General inhibition

of the conversion

of testosterone

into DHT by

targeting both

isoforms of 5α-

reductase.

Cessations of the

growth of

prostate.

Dutasteride Similar to finasteride

Muscarinic

antagonist

Inhibits M2 and

M3receptors

which have roles

in the control of

urinary bladder

function.

Releases urinary

difficulties,

including

frequent

urination and

inability to

control urination.

Tolterodine Blurred vision, dry

mouth, upset stomach,

headache, constipation,

dry eyes, dizziness

Source: American urological association guideline: Management of Benign

Prostatic hyperplasia, 2010

The effects of finasteride on prostate size have been studied extensively with maximal

(20%-33%) reduction of prostate volume achieved within 6 months (Gormley et al.,

1992). Effects may take longer to appear than alpha blockers, but may persist for more

duration (Roehrborn et al., 2004). When used together with alpha blockers, a reduction

of BPH progression to acute urinary retention and surgery has been noted in patients

with larger prostates(Trufakin et al., 2005). Side effects include decreased libido and

ejaculatory or erectile dysfunction (Gormley et al., 1992). In recent times phytotherapy

is being prescribed extensively for treatment of prostatic diseases, especially BPH.

Extracts of the berries of Dwarf American Palm (Saw Palmetto; Serenoa repens) and

bark of red stinkwood (Prunus Africana; Pygeum africanum) have been shown to be

extremely useful in the management of BPH without any major detectable side effects.

However, scientific evidence for treatment with these agents is very limited(Dreikorn,

2002).



2.2.7 Phytotherapy and BPH

Phytotherapy is increasingly being preferred by BPH patients because of its minimal

side-effects and safety in long term use. In men with BPH, evidences suggest that

several plant based therapies effectively improve urologic symptoms and flow

measures(Dreikorn, 2000), however, the scientific basis of such claims are very limited.

Table 2.2.2 Phytotherapies used for the management of BPH.(Curtis Nickel et al.,

2008)

Plant Name/ Origin Activecompounds Mechanisms/Suggested

Effects

Serenoa repens

(Sabal serrulata)

American dwarf palm

tree/saw palmetto berry

Free fatty acids

Phytosterols

(beta-sitosterol and others)

Aliphatic alcohols

Antiandrogen

↓ 5-alpha reductase

↓ growth factor

Anti-inflammatory

Pygeum africanum,

African plum tree

(Tadenan)

Phytosterols (beta

sitosterol, beta sitosterone)

Triterpenes

Long-chain fatty acids

↓ bFGF and EGF (induce

fibroblast proliferation)

↓ inflammation/edema

↓ LH, testosterone, prolactin

↓ detrusor contractility

Alters bladder function

Inhibits growth factors

Urticadioica

Nettleroot

Lectins, phenol,

sterols, lignans

↓ 5-alpha reductase

↓ growth factors

↓ ATPase

Quercetin

(extract from onions,

tea, spices, red wine,

cranberry, and citrus

fruits)

Bioflavonoid ↑ TGF beta (enhances

apoptosis)

Anti-inflammatory

↓ inflammation

Antioxidant-Inhibits

inflammatory

cytokines

↓ DHT

Hypoxis rooperi

South African star grass

Beta-sitosterol, other

phytosterols

↓ cell growth

Modulates SHBG

Cucurbita pepo

Pumpkin seed

Sterols, carotinoids,

minerals (Se, Mg)

Antiandrogen

Anti-inflammatory



Secale cereal

Rye pollen

Alpha amino acids,

phytosterols, carbohydrate

↓ urethral resistance

alpha receptor

*ATPase, adenosine triphosphatase; bFGF, basic fibroblast growth factor; DHT, dihydrotestosterone;

EGF, epidermal growth factor; LH, luteinizing hormone; Mg, magnesium; Se, selenium; SHBG, sex

hormone–binding globulin; TGF beta, transforming growth factor beta.

Clinical studies have shown that a standardized plant extract of Serenoa repens is

equipotent to tamsulosin (an α-blocker) and finasteride (a 5α-reductase inhibitor) in

improving IPSS, QoL and peak flow rate, but fares much better in terms of ejaculatory

disorders, libido and sexual potency(Carraro et al., 1996). This indicates that new leads

for safer anti-BPH drugs(Verma et al., 2014) can be identified from plant source.

2.3 Prostate cancer

Prostate cancer is a leading cause of cancer deaths in men. It is a disease ranging from

asymptomatic to a rapidly fatal systemic malignancy. The prevalence of prostate cancer

in some western populations is so high that it could be considered a normal age related

phenomenon and its incidence in Indian male is on the rise. Prostate cancer poses a

greater risk for American men, especially African-American men, than any other

nonskin cancer and is estimated to account for 220,900 new cancer diagnoses and

28,900 deaths, approximately 1 every 15 minutes(Jemal et al., 2003). Successful efforts

at early detection with the use of the serum prostate-specific antigen (PSA) test has

resulted in narrowing of the still enormous gap between the clinical incidence (8%

lifetime risk) and autopsy-based prevalence (80% by age 80 years). Most men die with

prostate cancer rather than from it, yet physicians are unable to stratify patients

accurately into those who will have progressive cancer and those who will not. An

equally great problem is determining which men are at greatest risk for developing

clinically apparent prostate cancer. An understanding of the risk factors for cancer has

practical importance for public health efforts and genetic and nutritional

education(Bostwick et al., 2004). The incidence of clinically detected prostate cancer

in American men is highest in the world(Morrison et al., 1995). European and Canadian

rates are lower than in the U.S., but these rates are rising and are expected to double in

the next few decades(Parkin and Muir, 1992). The lowest incidence rates



are in Asia and North Africa. This variation among populations may reflect the

underlying risk and the biologic behavior of resultant tumors. Dietary factors may

influence the risk of prostate cancer, and some factors may possess chemopreventive

and therapeutic potential in prostate cancer(Syed et al., 2008). Experimental evidence

suggests that dietary factors play a crucial role in prostate carcinogenesis by affecting

fundamental cellular processes involved in carcinogenesis, including apoptosis, cell-

cycle control, angiogenesis, inflammation, and DNA repair(Kumar et al., 2011).

2.3.1 Role of Telomerase in cancer

Telomerase is considered an almost universal target for human cancers since

telomerase-mediated telomere maintenance is the mechanism employed by a vast

majority of cancer cells to enable limitless proliferation. Telomeres are protective caps

at the ends of human chromosomes which gets shorten with each successive cell

division in normal human cells whereas, in tumors, they are continuously elongated by

human telomerase reverse transcriptase (hTERT). Telomerase is overexpressed in 80–

95% of cancers and is present in very low levels or is almost undetectable in normal

cells (Ruden and Puri, 2013). By de novo synthesizing TTAGGG repeats, telomerase

can maintain cancer cell telomeres at stable length at all times, ensuring their rapid

proliferating potential and immortal capacity. The key role in this process of the system

of the telomere length maintenance with involvement of telomerase is still poorly

studied. Undoubtedly, DNA polymerase is not capable of completely copying DNA at

the very ends of chromosomes; therefore, approximately 50 nucleotides are lost during

each cell cycle, which results in gradual telomere length shortening. Critically short

telomeres cause senescence, following crisis and cell death. Therefore, telomerase

upregulation is considered to be a critical step in cell tumorigenesis. The difference in

telomere lengths and telomerase activity in normal and cancer cells explains an induced

therapeutics cytotoxicity on cancer cells while having a minimal impact on normal cells

(Gomez et al., 2012). Although telomerase therapeutics are not approved yet for clinical

use, we can assume that based on the promising in vitro and in vivo results and

successful clinical trials, it can be predicted that telomerase therapeutics will be utilized

soon in the combat against malignancies and degenerative diseases. The active search



for modulators is justified, because the telomere/telomerase system is an extremely

promising target offering possibilities to decrease or increase the viability of the cell

for therapeutic purposes(Ruden and Puri, 2013)(Syed et al., 2008).

2.3.2 Risk Factors for Prostate Cancer

Endogenous risk factors for prostate cancer include the following:

2.3.2.1 Family history

Family history is associated significantly with prostate cancer risk in epidemiologic

studies but may be influenced by detection bias. The clinical and pathologic features of

familial cancer are similar to non-familial cancer(Heise and Haus, 2014).

2.3.2.2 Hormones

Androgens significantly alter prostate cancer growth rates, and the progression of

prostate cancer from preclinical to clinically significant forms may result in part from

altered androgen metabolism. Elevated concentrations of testosterone and its potent

androgenic metabolite, dihydrotestosterone, over many decades may increase prostate

cancer risk, but results have been inconsistent (Ragnarsson et al., 2013). Hormone

levels may be affected both by endogenous factors (e.g., genetics) and by exogenous

factors (e.g. exposure to environmental chemicals that affect hormone activity).

2.3.2.3Race

Differences in prostate cancer risk by race may reflect three factors: differences in

exposure, such as dietary differences (exogenous factors); differences in detection

(reflecting exogenous factors); and genetic differences (endogenous factors). The

highest incidence rates for prostate cancer in the world are among African-American

men, who have a higher risk of prostate cancer than white American men(Mahal et al.,

2014b). However, racial differences may reflect differences in access to care

(exogenous factors), differences in the decision-making process of whether to seek

medical attention and follow-up, and differences in allelic frequencies of microsatellites

at the androgen receptor (AR) locus or polymorphic variation(Mahal et al., 2014a).



2.3.2.4Aging and oxidative stress

Clinical studies indicate that intake of antioxidants, such as selenium, α-tocopherol

(vitamin E), and lycopene (a carotenoid) offers protection against prostate

cancer(Paschos et al., 2013; Rebillard et al., 2013). Our current knowledge of the

relation between aging and prooxidation- antioxidation homeostasis of the human

prostate remains virtually nonexistent.

Exogenous risk factors for prostate cancer include the following:

2.3.2.5 Diet

Descriptive epidemiologic studies of migrants, geographic variations, and temporal

studies have implicated a wide variety of dietary factors in the development of prostate

cancer. Fat consumption, especially polyunsaturated fat, shows a strong, positive

correlation with prostate cancer incidence and mortality, perhaps resulting from fat-

induced alterations in hormonal profiles, the effect of fat metabolites as protein or

DNA-reactive intermediates, or fat-induced elevation of oxidative stress(Pelser et al.,

2013; Richman et al., 2013). Retinoids, including vitamin A, help regulate epithelial

cell differentiation and proliferation, with a positive association with prostate cancer

risk. Vitamin C is a scavenger of reactive oxygen species (ROS) and free radicals, but

there is no consistent association of intake and prostate cancer risk(Paschos et al.,

2013). Vitamin D deficiency may be a risk factor for prostate cancer; the hormonal

form, 1-25- dihydroxyvitamin D, inhibits invasiveness and has antiproliferative and anti

differentiative effects on prostate cancer. Vitamin E (α-tocopherol) is an antioxidant

that inhibits prostate cancer cell growth through apoptosis, and daily intake decreased

the risk of prostate cancer by 32% in a large, controlled, clinical trial. Zinc (Zn)

concentration is higher in the prostate than in any other organ in the body; although it

is reduced ~ 90% in prostates with cancer; the



relation of dietary zinc and prostate cancer risk is uncertain. Selenium is an essential

trace element that inhibits viral and chemical, carcinogen-induced tumors in animals; a

chemo preventive role for selenium is plausible, but the evidence in humans is limited.

Alcohol intake has no significant association with prostate cancer risk. Consumption of

cruciferous vegetables is associated with a decreased risk of many cancers, but there is

no evidence of a protective effect for prostate cancer(G et al., 2013). Lycopene, an

abundant constituent of tomato based products and the most efficient carotenoid

antioxidant, has a significant protective effect.

2.3.2.6 Environmental agents

One class of environmental agents that has received a lot of attention is the endocrine

disrupting chemicals (EDCs). An EDC can be defined as an environmental agent that

positively or negatively alters hormone activity and ultimately leads to effects on

reproduction, development, and/or carcinogenesis, particularly of reproductive

organs(Albert et al., 2013; Castro et al., 2013). EDCs have been identified as those that

elicit effects on estrogen, androgen, and/or thyroid activities(Castro et al., 2013).

Although it has been shown that the majority of the well-studied EDCs are estrogen

agonists, which bind to estrogen receptors (ERs), thereby increasing estrogenic activity,

it has been shown that a number of EDCs affect other hormonal activities as well(Shah

et al., 2008). For example, it has been shown that the active metabolite of the pesticide

vinclozolin is an androgen antagonist, binding to the AR and decreasing the expression

of androgen-regulated genes (Wong et al., 1995).

2.3.3 Therapies for Prostate cancer

2.3.3.1 Androgen ablation therapy

The first line therapy for CaP patients is androgen deprivation, either by surgical or

medical castration. Androgen deprivation therapy is the mainstay of managing

advanced prostate cancer(Rove and Crawford, 2014). However, despite this therapy,

eventually all prostate tumors adapt to hormonal ablation therapy and progress. Some



evidence suggests that additional hormonal manipulations can be useful after primary

castration therapy. Indeed, non-steroidal androgen antagonists such as bicalutamide,

flutamide or nilutamide are able to further block androgen receptor(Fuse et al.,

2007)and inhibitors of the adrenal androgen production such as ketoconazole,

corticosteroids or aminoglutethiamide have been useful to inhibit testosterone

production in both testes and adrenal glands. However, in the long term, prostate cells

are able to grow in the absence of androgens. Although no curative therapies exist for

such refractory prostate cancers(Tsao et al., 2012), recent studies have demonstrated

that treatment with regimens containing docetaxel, a cytotoxic microtubule inhibitor,

modestly prolongs survival (2.5 months) in patients with metastatic, hormone refractory

prostate cancer(Chen et al., 2014); however, it is clear that more effective therapies that

target late stages of the disease are urgently required.

2.3.3.2 Selective Estrogen Receptor Modulators (SERMs)

The development of chemoprevention strategies against prostate cancer would have the

greatest overall impact both medically and economically against prostate cancer.

Estrogens are required for prostate carcinogenesis. Antiestrogens and selective estrogen

receptor modulators (SERMs) appear to delay and to suppress prostate

carcinogenesis(Steiner and Raghow, 2003). SERMs are generally considered to be

‘‘weak estrogens’’ because they possess both agonist and antagonist activities

depending on the specific tissue type and on the relative ER subtype interactions. The

ideal chemopreventive agent must have minimal or no side effects or toxicity to be

accepted by otherwise healthy men who are at risk for prostate cancer. SERMs do not

inhibit 5a-reductase activity or testicular 17α -hydroxy/C17, 20-lyase activities.

Toremifene has been shown to decrease prostate cancer incidence in the TRAMP

model(Raghow et al., 2002). Raloxifene has been shown to induce apoptosis in

androgen independent human prostate cancer cell lines(Kim et al., 2002; Kumar et al.,

2012). Both toremifene and raloxifene appear to mediate their effects through the ER

and are not dependent on androgen signaling. Toremifene has been evaluated in a phase

II exploratory trial in men with high-grade PIN.



Estrogen stimulates cellular proliferation through ER by inducing local production of

stimulatory peptide growth factors and therefore SERMs would be expected to decrease

the levels of these stimulatory growth factors and augment the production of TGF beta

the cellular microenvironment level. In addition, the antiproliferative effects of SERMs

may be mediated by other mechanisms including binding and sequestration of

calmodulin (Lam, 1984), inhibition of protein kinase C(O'Brian et al., 1985), and

induction of p21waf1I/cip1. SERMs have the ability to bind to ER-α and ER-ß,

competing with estradiol and other estrogens for binding to ERs in breast and prostate

tissues(Kuiper et al., 1997; Paech et al., 1997; Tremblay et al., 1997; Chang and Prins,

1999; Labrie et al., 1999). The formation of SERM-ER complexes results in the

inactivation of the estrogen-regulated genes, thereby decreasing cellular

proliferation(Steiner and Raghow, 2003).In the present study we have addressed the

problems of both benign prostatic hyperplasia and prostate cancer and have attempted

to identify some novel treatment/management modalities using both designed

molecules(Kumar et al., 2012) (modern drug candidates) and natural products from

plant source(Verma et al., 2014). Our studies have identified and mechanistically

elucidated some useful leads that may help in the development of new management

strategies for prostatic diseases.

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