review literature - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/62177/2...aromatase...
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REVIEW & LITERATURE
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VIKAS VERMA Review of Literature
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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.
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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
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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.
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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
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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).
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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
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(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
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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).
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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
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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
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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
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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).
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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
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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
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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.
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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.