Dietary phytochemicals popularly associated with health benefits often have a polyphenolic structure. Polyphenols invariably have an important protective role in plants - e.g. resveratrol, in the skin of red grapes, protects against fungal attack & damage caused by intense sunlight, while sulforaphane, DIM & PEITC in cruciferous vegetables, are released in response to physical cell damage. The strange thing is why these chemicals might also be useful in humans.
Usually, when health benefits of polyphenols are being discussed, the assumption is that the benefit is solely because they protect us against free radical damage. I will discuss the confusing anti-/pro-inflammatory PCa issue of polyphenols in a follow-up post. The primary reason to be interested in polyphenols in PCa, IMO, is that they are inhibitors of nuclear factor-kappa B [NF-kB].
NF-kB is present in cells in an inactive form. Under normal conditions, cells in the prostate, say, divide/die in such a way that the adult organ is in a state of dynamic equilibrium. If the prostate comes under bacterial or viral insult, cell death might begin to outrun cell division. In this situation, NF-kB would be activated, to primarily put a hold on cell death, so as to maintain organ size & function.
Once the crisis is over, things get back to normal. However, aging populations in the developed world are plagued with chronic disease, where NF-kB is constantly activated. Consequently, from rheumatoid arthritis to cancer, cell death is inhibited while cell division is permitted to continue.
Another hallmark of chronic disease is inflammation. This too is due to NF-kB activation. When NF-kB is activated, a great number of cell-survival proteins are upregulated. This includes pro-inflammatory COX & LOX enzymes.
Within the normal prostate cell, there is a structure called a lipid raft. This is where various lipids congregate, such as cholesterol. Lipid rafts also contain arachidonic acid [AA].
AA is often thought of as the evil omega-6, because of its role in inflammation. Some will not eat eggs because there is some AA. In fact, AA is a vital fatty acid. Mostly, the body makes what it needs from linoleic acid [LA]. Modern diets contain a lot of LA, and the assumption is that polyunsaturated cooking oils high in LA (such as corn oil) result in excess AA. However, the body will only make so much AA. The basic problem is that such oils disturb the omega-3:6 ratio. Marine omega-3 fatty acids can counter a pro-inflammatory state in the lipid raft, but there has to be a favorable 3:6 ratio to achieve this.
In PCa, the ultimate problem is not the presence of AA (there has to be some), but NF-kB activation.
Cyclooxygenase (COX) enzymes act on AA to create the 2-series prostaglandins and thromboxanes. Lipoxygenase (LOX) enzymes act on AA to create the 4-series leukotrienes.
These AA derivatives are responsible for pro-inflammatory functions which includes platelet aggregation and clot formation & Interleukin-6 (IL-6) production - &, ultimately, progression.
Naturally, these arachidonic acid metabolites are much studied. Here is a small sample of papers.
[3] Prostaglandins.
[3a] "Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer (PCa). Our study in both cultured cells and PCa patients reveals a novel pathway for the actions of genistein, namely the inhibition of the synthesis and biological actions of prostaglandins (PGs), known stimulators of PCa growth. In the cell culture experiments, genistein decreased cyclooxygenase-2 (COX-2) mRNA and protein expression in both human PCa cell lines (LNCaP and PC-3) and primary prostate epithelial cells and increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA levels in primary prostate cells. As a result genistein significantly reduced the secretion of PGE2 by these cells. EP4 and FP PG receptor mRNA were also reduced by genistein, providing an additional mechanism for the suppression of PG biological effects. Further, the growth stimulatory effects of both exogenous PGs as well as endogenous PGs derived from precursor arachidonic acid were attenuated by genistein. We also performed a pilot randomized double blind clinical study in which placebo or soy isoflavone supplements were given to PCa patients in the neo-adjuvant setting for 2 weeks prior to prostatectomy. Gene expression changes were measured in the prostatectomy specimens. In PCa patients ingesting isoflavones, we observed significant decreases in prostate COX-2 mRNA) and increases in p21 mRNA. There were significant correlations between COX-2 mRNA suppression, p21 mRNA stimulation and serum isoflavone levels. We propose that the inhibition of the PG pathway contributes to the beneficial effect of soy isoflavones in PCa chemoprevention and/or treatment."
[3b] "We present an overview of the prostaglandin (PG) pathway as a novel target for the treatment of prostate cancer (PCa) using a combination of calcitriol and genistein, both of which have known antiproliferative properties. Calcitriol inhibits the PG pathway in PCa cells in 3 separate ways: by decreasing cyclooxygenase-2 (COX-2) expression, stimulating 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression, and decreasing EP (PGE2) and FP (PGF(2alpha)) receptors. These actions of calcitriol result in reduced levels of biologically active PGE2, leading ultimately to growth inhibition of the PCa cells. We also demonstrate the advantages of using calcitriol in combination with genistein for the treatment of PCa. Genistein, a major component of soy, is a potent inhibitor of the activity of CYP24, the enzyme that initiates the degradation of calcitriol. This leads to increased half-life of bioactive calcitriol, thereby enhancing all of calcitriol's actions including those on the PG pathway. In addition to inhibiting CYP24 enzyme activity, genistein has its own independent actions on the PG pathway in PCa cells. Like calcitriol it inhibits COX-2 expression and activity, leading to decreased synthesis of PGE2. It also inhibits the EP and FP receptors, thereby reducing the biological function of PGE2. Thus, the combination of calcitriol and genistein acts additively to inhibit the PG pathway. Both calcitriol and genistein are relatively safe and have little toxicity associated with their intake. We postulate that the combination of calcitriol and genistein is an attractive therapeutic option for the treatment of PCa."
[4] Thromboxanes.
[4a] "Thromboxane A(2) ... is a prostanoid formed by thromboxane synthase using the cyclooxygenase product prostaglandin H(2) as the substrate. Previously, increased expression of thromboxane synthase was found in prostate tumors, and tumor cell motility was attenuated by inhibitors of thromboxane synthase."
[4b] "The expression levels of COX-2, {thromboxane A(2) synthase}, and {thromboxane A(2) receptors} were significantly higher in malignant than in corresponding nontumoral prostatic epithelial cells."
"Proteins specifically involved in the {thromboxane A(2)} pathway are up-regulated in human PCa and their level of expression is associated with tumor extraprostatic extension and loss of differentiation."
[5] Leukotrienes.
[5a] MK591 is a second-generation leukotriene biosynthesis inhibitor - in fact, it is a 5-LOX inhibitor.
"We observed that MK591 effectively kills the bone-invading C4-2B human prostate cancer cells (which bear characteristics of CRPC), but does not affect normal, non-cancer fibroblasts (which do not express 5-Lox) in the same experimental conditions."
"Effect of MK591 on invasion and soft-agar colony formation by C4-2B cells at sub-lethal doses reminds that this agent may possess the capability of stopping the dispersal as well as new colony formation of prostate cancer cells at distant sites which are typical characteristics of the metastasis process".
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A while back, I posted a series on inflammation markers & the effect on survival. There are a number of studies related to therapies that show poorer response & survival when inflammation markers are elevated before treatment. The study papers always conclude that the markers can be used for prognosis, but they miss the point. Both the markers & the prognosis are due to NF-kB activation. Inhibit NF-kB & we inhibit both the markers & the stimulus for PCa aggression.
...
Professor Tom Gilmore's lab at Boston University maintains a nice NF-kB site [1]. The list of "Antioxidants that have been shown to inhibit activation of NF-kB", which includes polyphenols, needs to be brought up to date [2], but has useful links to studies.
...
The remainder of this post is lifted from a review of polyphenols in PCa research:
"This section provides an overview of selected dietary polyphenols (based on their subclasses) which have been used in studies directed towards PCa prevention and treatment.
3.1. Phenolic Acids
Phenolic acids are composed of hydroxy-cinnamic and hydroxy-benzoic acids and account for 30% of dietary polyphenols [7]. They are ubiquitous to plant material and sometimes present as esters and glycosides. They have anti-oxidant activity as chelators and free radical scavengers with special impact over hydroxyl (–OH) and peroxyl radicals, superoxide anions, and peroxynitrites. Gallic acid, one of the most studied and promising compounds in PCa research, belongs to the hydroxy-benzoic group. Gallic acid is the precursor of many plant-derived tannins, while cinnamic acid is the precursor of hydroxy-cinnamic acids [14,15].
3.1.1. Anacardic Acid
Anacardic acid (AA; 6-pentadecylsalicylic acid) is the active phenolic lipid found in the Amphipterygium adstringens plant. It possesses anti-inflammatory, anti-cancer, anti-oxidative and anti-microbial functions. The bark of this plant is widely used in traditional medicines for treatment of gastric ulcers, gastritis and stomach cancers [16]. In PCa, AA is reported as a natural inhibitor of non-specific histone acetyltransferase and has been shown to inhibit prostate tumor angiogenesis by targeting the proto-oncogene tyrosine-protein kinase (Src)/focal adhesion kinase (FAK)/rhodopsin (Rho) guanosine triphosphate (GTP)ase signaling pathway [17]. AA affects multiple steps of tumor angiogenesis including endothelial cell viability, migration, adhesion, and differentiation both in vitro and in vivo. The AA-mediated effect and mechanism on PCa cells is based on its ability to inhibit cell proliferation and induce G1/S cell cycle arrest and apoptosis. AA inhibits androgen receptors (AR), activates tumor suppressor protein p53 and cyclin-dependent kinase (CDK) inhibitor-1/p21, and regulates the transcription of other related target genes [18].
3.1.2. Caffeic Acid
Caffeic acid (CA; 3,4-dihydroxycinnamic) is one of the hydroxy-cinnamate metabolites universally present in plant tissues. CA is found in many food sources, including coffee drinks, blueberries, apples and cider. Besides acting as a cancer inhibitor [19,20], it also possesses anti-oxidant and anti-bacterial activities in vitro and can contribute to the prevention of atherosclerosis and other CVDs [21]. CA has been reported to inhibit AR signaling and subsequent inhibition of cell proliferation of human androgen-dependent PCa cells.
Some derivatives of CA have also shown potent cytotoxic and anti-proliferative effects and dihydrotestosterone (DHT)-stimulated prostate specific antigen (PSA) secretion [22]. CA-phenyl ester (CAPE) enhances anti-proliferative and cytotoxic effects of docetaxel (DOC) and paclitaxel (PTX) in PCa cells attributed to CAPE augmentation of DOC and PTX proapoptotic effects in addition to CAPE-induced alterations in estrogen receptors (ER)-α and ER-β abundance [23,24]. CAPE significantly reduced protein kinase-B/Akt, extracellular signal-regulated kinases (ERK), and ER-α phosphorylation. CAPE-mediated inhibition of Akt phosphorylation was more prominent in cells expressing ER-α such as PC3 compared to LNCaP. CAPE suppressed the proliferation of LNCaP, DU145, and PC3 human PCa cells in a dose-dependent manner.
Overexpression of Akt1 and c-Myc significantly blocked the antiproliferative effects of CAPE. CAPE administration may be useful as an adjuvant therapy for cancers that are driven by the p70S6K and Akt signaling networks [25]. CAPE, a known inhibitor of NFκB can inhibit interleukin (IL)-6 secretion induced by tumor necrosis factor (TNF)-alpha, thereby suppressing signal transducers and activators of transcription (STAT)-3 translocation [26]. CAPE treatment suppressed proliferation, colony formation, and cell cycle progression in PC3 cells. CAPE decreased protein expression of cyclin D1, cyclin E, SKP2, c-Myc, Akt1, Akt2, Akt3, total Akt, mammalian target of rapamycin (mTOR), B-cell lymphoma (Bcl)-2, retinoblastoma protein (Rb), as well as phosphorylation of Rb, ERK1/2, Akt, mTOR, glycogen synthase kinase (GSK)3α, GSK3β, and PDK1, but increased protein expression of KLF6 and p21Cip1 in PC3 cells [27]. Taken together, evidence shows that CA has multiple protective effects, which can be further explored and developed towards PCa chemoprevention.
3.1.3. Ellagic Acid
Ellagic acid (EA; 4,4',5,5',6,6'-Hexahydroxydiphenic acid) is a polyphenolic compound present in fruits and berries such as pomegranates, strawberries, raspberries, and blackberries. It has anti-carcinogenic, anti-oxidant and anti-fibrosis properties. It is responsible for more than 50% of the anti-oxidant activity of pomegranate juice and for the beneficial effects of EA in PCa [28,29,30,31]. EA treatment of LNCaP cells induced a significant decrease in heme oxygenase (HO)-1 and -2, cytochrome P450 (CYP) 2J2 expression, and vascular endothelial growth factor (VEGF) and osteoprotegrin (OPG) levels. Similarly, CYP4F2 and CYPA22 were significantly downregulated by EA treatment, suggesting that EA interfered with multiple biological processes involved in angiogenesis and metastasis in PCa cells [32].
Recently, apoptotic pathways involved in EA-mediated chemoprevention were reported. Apoptosis was induced by downregulation of anti-apoptotic proteins, SIRT1, HuR, and HO-1. EA modulated apoptosis inducing factor (AIF), resulting in an increase in ROS levels and caspase (CASP)-3, while reducing transforming tumor growth factor (TGF)-β and IL-6 [33]. EA reduced proliferation by inhibiting mTOR and decreasing levels of β-catenin. EA slightly decreased matrix metalloproteinase (MMP)-2 but had no effect on MMP-9 in PC3 cells. Non-toxic concentration of EA was shown to inhibit invasion and motility of PCa cells through its action on protease activity [34]. Treatments with EA induced differentiation by causing significant reduction in chromogranin-A, p-Rb, DNMT-1, and p-Akt levels, along with increased p75 neurotrophin receptor expression. EA also induced DNA damage in PCa cells in a dose-dependent manner [35]. Pomegranate juice (PJ) containing EA, along with other components, has been shown to inhibit PCa metastasis.
Two initial exploratory clinical studies investigating proprietary pomegranate products reported a trend of effectiveness in increasing PSA doubling time in patients with PCa [36,37]; however, another clinical study did not support these results [38]. Recently, a group evaluated the PJ blends to investigate the contrasting clinical evidence between these two studies. Their results showed that daily doses of PJ in the latter study contained very little concentrations of gallic acid and punicalagin compared to the concentrations found in the earlier two studies. The authors confirmed that not just pomegranate but the amount of co-active compounds in the PJ blend along with EA was responsible for its clinical effectiveness [39].
3.1.4. Gallic Acid
Gallic acid (GA; 3,4,5-trihydroxybenzoic acid) is ubiquitously present either in free form or, more commonly, as a constituent of tannins, namely gallotannins [40]. Some of the natural products found in nature that are rich in GA are strawberries, pineapples, bananas, lemons, red and white wines, gallnuts, sumac, witch hazel, tea leaves, oak bark and apple peels [41]. Biologically, GA possesses anti-bacterial, anti-viral, anti-inflammatory, and anti-oxidant properties [41,42,43,44]; anti-melanogenic activity is also present via the inhibition of tyrosinase activity [45]. Anti-cancer activity of GA has been reported in leukemia, oral tumor and esophageal cancer cells [46,47]. GA inhibited cell viability in DU145 and 22Rν1 PCa cells in a dose-dependent manner via induction of apoptosis [48].
Regarding GA’s ability against PCa, studies have shown both anti-cancer and cancer chemopreventive effects in human PCa DU145 cells in vitro and the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, respectively [49,50]. GA inhibited the tumor growth in DU145 and 22Rν1 PCa xenografts in nude mice and decreased microvessel density, as compared to controls in both models [51]. Penta-O-galloyl-beta-d-glucose (5GG), which consists of a glucose molecule on which five –OH groups are esterified with GA, has been shown to suppress tumor growth via inhibition of angiogenesis [52] and STAT-3 activity in PCa cells [53]. 5GG arrested cells at the G1 phase, induced apoptosis, inhibited lipopolysaccharide-induced NFκB activation, fatty acid synthase (FAS) expression and suppressed cell invasion by reducing MMP-9 expression [54].
Mechanistic studies of 5GG-mediated regulation of MMP-9 showed activation of EGF-induced c-jun N-terminal kinase and subsequent suppression of NFκB nuclear translocation. 5GG also reduced epidermal growth factor receptor (EGFR) expression through the proteasome pathway and suppressed invasion and tumorigenesis in nude mice implanted with PC3 cells [55]. 5GG’s role as a novel inhibitor of DNA polymerases was studied and the results showed that 5GG induced PCa S-phase arrest through DNA replicative blockage and induced G1 arrest via cyclin D1 downregulation [56]. Another analog of GA, theaflavin-3-3'-digallate (TF3), and 5GG together showed inhibition of rat liver microsomal 5alpha-reductase activity, which catalyzes the conversion of testosterone to a more active androgen, DHT which then subsequently binds to AR and functions inside the nucleus to regulate specific gene expression. Furthermore, TF3 and 5GG reduced androgen-responsive LNCaP cell growth, inhibited expression of AR, and lowered androgen-induced PSA and FAS protein levels.
3.2. Stilbenes
Stilbenes or stilbenoids are a well-known class of naturally occurring polyphenols. Stilbenes are chemically characterized by their core structure of 1,2-diphenylethylene. Most stilbenes are stress metabolites produced in plants and act as anti-fungal phytoalexins, compounds that are only synthesized in response to an infection or injury. These plant defense compounds have tremendous potential in biological and cellular processes applicable to human health [57]. Stilbenes are reported to be potentially important cancer chemoprotective agents, being able to inhibit cellular events associated with carcinogenesis, including tumor initiation, promotion, and progression [58].
3.2.1. Piceatannol
Piceatannol (PT; trans-3,4,3',5'-tetrahydroxystilbene) is a naturally occurring polyphenol present in rhubarb, berries, peanuts, sugar cane, wine and grape skins. PT, a metabolite biotransformed from resveratrol (RSV), has been demonstrated to exert anti-inflammatory, anti-carcinogenic and cardioprotective effects [59]. In silico and biochemical analyses have identified quinone reducatase 2 (QR2) as a target of PT. PT-mediated inhibition of cell proliferation and induction of apoptosis was comparable to RSV. PT interacted with QR2 at the same site as RSV, forming an H-bond with asparagine-161. The anti-cancer effect of PT observed in PCa cells was shown to be QR2-dependent, as PT-mediated inhibition of proliferation and QR2 activity were much lower in QR2-knockdown cells relative to QR2 expressing cells. The study suggested PCa prevention by RSV to be partially attributed to its conversion to PT [60].
PT inhibits the migration/invasion of DU145 PCa cells possibly mediated by decrease in IL-6/STAT-3 signaling [61]. PT delayed G1 cell cycle progression of DU145 cells via the inhibition of CDK2 and CDK4 [62]. PT was found to induce apoptosis in DU145 human PCa cells via activation of extrinsic death receptors and intrinsic mitochondrial-dependent pathways [63]. Recently a study showed that inhibition of MMP-9 by PT decreased the invasive potential of DU145 cells. PT inhibits TNF-α-induced invasion by suppression of MMP-9 activation via Akt-mediated NFκB pathways in DU145 PCa cells [64]. Another study showed in vivo evidence that PT, when administered orally, inhibits tumor formation, growth, and diminished cell colonization in LNCaP PCa xenografts [65]. PT has been shown to suppress the activation of some transcription factors including NFκB, which plays a central role as a transcriptional regulator in response to cellular stress caused by free radicals, ultraviolet radiation, cytokines, or microbial antigens.
PT inhibits Janus kinase-1 (Jnk-1), a key member of the STAT pathway crucial in controlling cellular activities in response to extracellular cytokines, and is involved in inflammation and carcinogenesis. The anti-tumor, anti-oxidant, anti-inflammatory, and pharmacological properties of PT suggests that PT might be a potential biomolecule for PCa prevention; however, more data are needed on its bioavailability and toxicity in humans [66].
3.2.2. Pterostilbene
Pterostilbene (PTER; trans-3,5-dimethoxy-4-hydroxystilbene), an anti-oxidant found mainly in berries and grapes, has gained much attention due to its chemopreventive and potential therapeutic effects reported in a variety of cancer types [67]. PTER-isothiocyanate, a conjugate of PTER inhibits the AR-regulated pathways in PCa cells. The conjugate significantly repressed cell proliferation, induced apoptosis by modulating phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/ERK pathways, arrested cell cycles, abrogated DHT induced activation, and down regulated AR expression in LNCaP cells [68]. PTER treatment inhibited cell proliferation in a dose-dependent manner in p53 wild type LNCaP and p53 null PC3 cells. PTER activated adenosine monophosphate-activated protein kinase (AMPK) in both p53 positive and negative human PCa cells, resulting in a decrease in activity and expression of lipogenic enzymes FASN and acetyl-CoA carboxylase (ACC). PTER increased the expression level of p53 and subsequently enhanced the expression level of p21, resulting in cell-cycle arrest in LNCaP cells. It is proposed that induction of p21 promoted growth arrest and exerted a protective affect after AMPK activation [69].
PTER induced apoptosis, cell cycle, and PSA in the human androgen-responsive LNCaP cells [70]. The effects of PTER against PCa were also studied in highly metastatic androgen-independent LNCaP cells and showed that PTER is an effective inducer of apoptosis based on flow cytometry and microscopic analysis of cell surface morphology. The authors investigated PTER’s effect upon three specific markers of mitochondrial apoptosis—Bcl-2, BAX and CASP-3—and found that pterostilbene decreased Bcl-2 expression by 2- to 2.5-fold and increased expression of BAX and CASP-3 by 2- and 3-fold, respectively [70]. This study reported PTER inhibits cell viability in LNCaP cells and causes cell cycle arrest at the G1/S-phase after 72 h of treatment. Furthermore, the anti-carcinogenic effects of PTER were seen upon two CDK inhibitors, CDNK1A and CDNK1B, which are essential to G1/S-phase regulation. PTER was found to up-regulate both CDNK1A and CDNK1B at a concentration of 25 μM in LNCaP cells. PTER treatment inhibited elevated PSA mRNA expression in LNCaP cells with a minimal concentration of 1 μM [70]. Further, PTER treatment inhibited elevated PSA levels that were hormonally induced groups, DHT and 17β-estradiol. PTER decreased Akt activation, MMP expression, and further contributed to anti-carcinogenesis. Akt and MMP are both associated with cancer cell proliferation and metastasis and down-regulated expression of the cancer marker α-methylacyl-CoA racemase.
A recent study demonstrated that dietary stilbenes are effective regulators of metastasis-associated protein (MTA1)/nucleosome, remodeling deacetylase-mediated p53 acetylation, apoptosis, and angiogenesis in PCa xenografts [71]. MTA1 has the additional advantage of being sensitive to pharmacologically safe dietary compounds. On the basis of strong in vitro and in vivo evidence, the authors proposed PTER to be explored as a lead compound for potent target-specific treatment of MTA1-overexpressing advanced PCa. PTER increased glutathione (GSH) peroxidase, GSH reductase and total GSH by 1.4-, 1.6-, and 2.1-fold, respectively. Furthermore, PTER increased levels of ROS by 5-fold and nitric oxide production by 6-fold. These findings indicated that PTER modified the anti-oxidant profile of PCa cells, leading to a cellular environment that is conducive to apoptosis [72]. Based on these cumulative findings, PTER possesses potent effects in both hormonal-responsive and hormonal-independent PCa in vitro and in vivo, suggesting its chemotherapeutic implications in PCa.
3.2.3. Resveratrol
Resveratrol (RSV; 3,4',5-trihydroxystilbene), one of the best studied stilbenes, is found largely in grapes, blueberries, peanuts, pistachios and hops. A product of grapes, red wine also contains significant amounts of RSV [10,73]. RSV exists both in cis- and trans-stereoisomeric forms of which the trans-isomer is biologically active [74,75]. RSV induces a broad range of effects on cell phenotypes. Ample evidence on RSV indicates inhibition of cancer cell growth, induction of cell cycle arrest, and apoptosis in various PCa cell lines [76,77,78]. RSV is known to induce differentiation in certain cell types [79,80,81].
COX-2 catalyzes the conversion of free arachidonic acid to prostaglandins, which can stimulate cell proliferation, promote angiogenesis, and suppress apoptosis, all of which promote malignancy [82,83,84]. RSV expresses anti-inflammatory activity by directly inhibiting COX-2 activity and suppressing NFκB by up-regulating MAPK-phosphatase-5 [85,86]. RSV has also been reported to reduce expression of MMPs, which are responsible for tumor invasion and metastasis and also decreases the levels of VEGF, resulting in angiogenesis inhibition [87,88,89,90,91]. RSV has the ability to increase sensitivity of PCa cells to ionizing radiation, which has potential, in combination with radiotherapy, for clinical applications [92,93,94,95,96,97].
Another recent report suggests Zn, in combination with RSV, as a novel approach for PCa management. Zn is abundantly available in healthy prostates, but with PCa progression, it reduces significantly [98]. RSV, in combination with Zn, was reported to increase the total cellular Zn and intracellular free labile Zn in normal human prostate epithelial cells [99]. In addition, an increase of Zn levels in plasma was reported in healthy adult rats administered with RSV. These studies suggest that RSV may influence Zn homeostasis, possibly via enhancing intracellular Zn accumulation [100]. The anti-cancer potential of RSV has been summarized in many in vitro and in vivo studies previously published [101]. RSV is well tolerated, but an optimal dose has not yet been determined. Another study recently confirmed that even though RSV has shown anti-cancer potential in various experimental studies reported to date, there is so far no concrete evidence to support the use of the compound for PCa treatments outside of clinical trials. The main reason for this caveat is that there is not enough clinical evidence to justify a recommendation for the prophylactic administration of RSV [102].
3.3. Stilbenes
Curcuminoids, curcumin, and their structurally related compounds are comprised of phenolic yellowish crystalline powder and are used to provide flavor and color to spice blends. Nutraceuticals (foods with medicinal potential) are prepared and consumed all across the world and are active in the prevention and treatment of various diseases including PCa [103]. Curcuminoids found in turmeric contain three principal components—curcumin, demethoxycurcumin and bisdemethoxycurcumin—of which curcumin is the most abundant and potent [104,105,106,107].
3.3.1. Curcumin
Curcumin and its derivatives have been reported to possess anti-inflammatory, anti-oxidative and anti-carcinogenic properties [108]. Curcumin was shown to inhibit proliferation in both androgen-dependent and androgen-independent PCa cell lines [109]. Curcumin inhibited several cell signaling pathways including NFκB, TNFR pathways. Curcumin and its derivatives demonstrated anti-cancer properties by inhibiting enzymes like COX-2, MMPs, mTOR, protein kinase C, and EGFR [110,111,112,113,114]. Curcumin inhibits PCa cell viability and induces cell apoptosis. The authors report that curcumin downregulates the expression of the inhibitor of DNA binding (Id)-1 mRNA and protein in PC3 cells, a key signaling molecule in PCa carcinogenesis and metastatic progression [115]. Curcumin was shown to inhibit proliferation and migration of human PCa cells.
Curcumin significantly suppressed phosphorylation of ERK1/2 and VEGF expression modulating the osteopontin/integrin-αvβ3 signaling pathway. It also caused MMP-9 activation associated with angiogenesis via regulation of secretion of VEGF and angiostatin in PC3 cells [116]. Curcumin analogues have been reported to be more effective in inhibiting human PCa cells and to retard the growth of human PC3 xenografts in immuno-compromised mice, as compared to curcumin alone [117,118]. Curcumin as a modulator of ER activity is an effective agent and has demonstrated protection against PCa invasion and metastasis [119]. Several in vitro and in vivo studies have provided evidence regarding the efficacy of curcumin against PCa; however, further studies directed towards the development of curcumin analogues/nanoparticles are needed, through which bioavailability of curcumin may be enhanced for prevention or reducing the development of PCa [120,121].
3.3.2. Demethoxycurcumin and Bisdemethoxycurcumin
Demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), analogs of curcumin, have been reported to modulate inflammatory signaling and cell proliferation to the same extent as curcumin. The relative potency for suppression of TNF-induced NFκB activation reported is curcumin > DMC > BDMC, suggesting the critical role of methoxy groups on the phenyl ring of curcumin. DMC and BDMC induced GSH to a similar extent as curcumin. Production of GSH correlates with suppression of NFκB activation and induction of cell proliferation through a ROS independent mechanism [122]. DMC has been reported to show the most efficient cytotoxic effects on PC3 cells. DMC activates AMPK and decreases activity of lipogenic enzymes FASN and ACC. DMC downregulates heat-shock protein (HSP)-70 and increases the activity of CASP-3. In addition, DMC treatment activates AMPK in PCa cells, which, in turn, regulated the HSP70/EGFR pathways. These findings demonstrate that AMPK pathways have a significant influence on DMC-mediated inhibition of tumor viability [123]. DMC inhibits migration of PC3 cells in both a dose- and time-dependent manner. DMC has also been reported to prevent against proliferation and apoptosis of PCa cells via CASP-3 routes. The activity of MMP-2 is suppressed, suggesting correlation between migration and invasion of PCa cells [124].
3.4. Flavonoids
Flavonoids comprise over 4000 varieties and account for about 60% of structurally-related dietary polyphenols, which are widely present in plants and ingested in varying degrees in the diet. Their chemical structure contains 2-benzene rings linked to three carbon atoms that form an oxygenated heterocycle [125]. Flavonoids are classified into flavonols, flavones, isoflavones, anthocyanidins, chalcones, and dihydrochalcones. The flavonols themselves are subdivided into cathechins, proanthocyanadins, theaflavins, and thearubigins [126]. Several beneficial properties have been attributed to these dietary compounds, including anti-oxidant, anti-inflammatory, and anti-carcinogenic effects. Flavonoids have shown potential to protect against viral infections, as well as several diseases such as diabetes, CVDs, inflammatory and neurological diseases [127,128].
3.4.1. Apigenin
Apigenin (APG; 4',5,7,-trihydroxyflavo
Effects of Curcumin and Lactoferrin to Inhibit the Growth and Migration of Prostatic Cancer Cells
p53 mutant-type in human prostate cancer cells determines sensitivity to phenethyl isothiocyanate (Watercress) induced growth inhibition
