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Review
, 20 (5)

Molecular Mechanisms and Bioavailability of Polyphenols in Prostate Cancer

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Review

Molecular Mechanisms and Bioavailability of Polyphenols in Prostate Cancer

Teodora Costea et al. Int J Mol Sci.

Abstract

Prostate cancer is the one of the most frequently diagnosed cancers among men over the age of 50. Several lines of evidence support the observation that polyphenols have preventive and therapeutic effects in prostate cancer. Moreover, prostate cancer is ideal for chemoprevention due to its long latency. We propose here an equilibrated lifestyle with a diet rich in polyphenols as prophylactic attempts to slow down the progression of localized prostate cancer or prevent the occurrence of the disease. In this review, we will first summarize the molecular mechanisms of polyphenols in prostate cancer with a focus on the antioxidant and pro-oxidant effects, androgen receptors (AR), key molecules involved in AR signaling and their transactivation pathways, cell cycle, apoptosis, angiogenesis, metastasis, genetic aspects, and epigenetic mechanisms. The relevance of the molecular mechanisms is discussed in light of current bioavailability data regarding the activity of polyphenols in prostate cancer. We also highlight strategies for improving the bioavailability of polyphenols. We hope that this review will lead to further research regarding the bioavailability and the role of polyphenols in prostate cancer prevention and treatment.

Keywords: bioavailability; dietary polyphenols; molecular mechanisms; prostate cancer.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Antioxidant and pro-oxidant effects of polyphenols in prostate cancer. Polyphenols can act as both antioxidant molecules, by free radical scavenging, and as pro-oxidant agents, by increasing ROS production—the mechanisms are dependent on the concentrations applied. In addition, polyphenols are able to increase the level of antioxidant enzymes in prostate cancer cell lines or in animal models of prostate cancer.
Figure 2
Figure 2
Chemical structures of some polyphenols that display similarities to dihydrotestosterone (DHT).
Figure 3
Figure 3
The effects of polyphenols on signaling pathways in prostate cancer. In the canonical pathway ARs are activated by DHT binding. AR can be transactivated in the absence of DHT through different signaling pathways: increased activity of RTK or interleukin receptors and their signaling pathways, modifications of the coregulatory proteins, or constitutively activated AR [115,126]. Ligand binding to RTK activates PI3K/Akt kinases, which trigger the activation of IKK. This pathway induces phosphorylation of IκB, resulting in its ubiquitylation and proteasome-mediated degradation. NF-κB is maintained in the cytoplasm by the interaction with IκB, and degradation of IκB activates NF-κB, which in turn is enabled to enter the nucleus and activate the genes involved in cell survival [127,128]. For simplification, the canonical pathway of NF-κB activation that takes place through the members of tumor necrosis factor receptors or interleukin receptors is omitted from the figure [129]. Similarly, the canonical pathway of PI3K/Akt signaling is not presented. Polyphenols might modulate the levels of signaling molecules in prostate cancer by decreasing or increasing their levels. Polyphenols downregulate AR (quercetin, genistein, resveratrol, EGCG), HSP90 (genistein), IGF-1 (apigenin), EGFR (curcumin, resveratrol), HER2 (resveratrol), ERK (apigenin, gallic acid, EGCG), phosphorylated PI3K (apigenin, curcumin, resveratrol), phosphorylated Akt (apigenin, CAPE, gallic acid, resveratrol), FoxO (apigenin), NF-κB (apigenin, curcumin, gallic acid, EGCG), GSK-3β (CAPE), VEFG (apigenin, genistein, quercetin, EGCG), uPA (apigenin), MMPs (apigenin, gallic acid, EGCG, genistein) and upregulate PTEN (resvetratol) and E-cadherin (apigenin). Legend: AR, androgen receptors; T, testosterone; DHT, dehydrotestosterone; HSP, heatshock protein; RTK, receptor tyrosine kinase; Raf, rapid accelerated fibrosarcoma protein; MEK, mitogen activated protein kinase, kinase; ERK1/2, extracellular signaling regulate d kinase; EGF, epidermal growth factor; IGF-1, insulin-like growth factor 1; HGF, hepatocyte growth factor; VEGF, vascular endothelial growth factor; PI3K, phosphoinositide 3 kinase; Akt, Ak thymoma protein-kinase (protein kinase B); NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IκB, inhibitor of κB; IKK, IκB kinase; FoxO, forkhead box O protein; PTEN, phosphatase and tensin homolog; Wnt, wingless/integrated ligand; GSK-3β, glycogen synthase kinase-3β; APC, adenomatous polyposis coli; TF, transcription factors; CAPE, caffeic acid phenethyl ester; EGCG, epigallocatechin gallate; upregulation (red ↑), downregulation (red ↓).
Figure 4
Figure 4
Cell cycle and the inhibitory effect of polyphenols in prostate cancer cells. DNA damage triggers the activation of the tumor suppressor and checkpoint proteins, while mitogen signals induce the progress of the cell through the cell cycle [136]. The following molecules are reported to be downregulated by polyphenols in prostate cancer: cyclin D (apigenin, caffeic acid phenethyl ester, gingerol), cyclin E (caffeic acid phenethyl ester, gingerol, quercetin), CDK2 (quercetin), CDK4 (gingerol), cdc25 (gallic acid). Polyphenols upregulate proteins coded by tumor suppressor genes, such as p53 (apigenin, curcumin, EGCG), p21 (apigenin, EGCG), p27 (apigenin) and checkpoint proteins CHK1, 2 (gallic acid). Moreover, administration of polyphenols induced the cell cycle arrest in a cell-line- and compound-dependent manner, particularly G2/M arrest (apigenin, gallic acid), G0/G1 arrest (EGCG, quercetin). Legend: cyclin-dependent kinases (CDK), retinoblastoma protein (RB), transcription factor E2 (E2F), mitosis (M), gap 1 phase (G1), gap 2 phase (G2), DNA synthesis phase (S), CHK, checkpoint proteins; cdc25, cell cycle division protein 25; upregulation (red ↑); downregulation (red ↓).
Figure 5
Figure 5
Apoptosis can be modulated by the activity of polyphenols in prostate cancer. Induction of apoptosis takes place through three main mechanisms: extrinsic, intrinsic, and perforin/granzyme pathways [145]. In the extrinsic pathway, activation of transmembrane death receptors (Fas/TNFR/DR) by their ligands (FasL/TNFα/TRAIL) induces the recruitment of FADD and further results in triggering of caspase-8 action. Mitochondrial release of cytochrome c, provoked by the truncated BID protein, induces the formation of the apoptosome and activation of caspase-9, which in turn activate caspase-3 and -7. The intrinsic pathway cross-talks with the extrinsic pathway at the mitochondrial level, where the BH-3 family of proteins (Noxa, Bmf, Puma, Hkr, Bik, etc.) promotes apoptosis through Bax/Bak assembly. The regulation of the apoptotic pathways is coordinated by the Bcl-2 family of proteins, which consists of both pro-apoptotic members (Bax, Bak) and anti-apoptotic members (Bcl-2). The cytotoxicity mediated by immune cells (i.e., cytotoxic T lymphocytes) occurs through pore formation in the membrane of the target cells. This pore can be formed with the help of pore-forming proteins (perforin) and is used to deliver proteases (granzymes), which in turn will trigger the apoptotic pathway [145,153]. The pro-apoptotic molecules that are upregulated by polyphenols in prostate cancer are caspase-3 (apigenin, gallic acid, gingerol, EGCG, quercetin), caspase-8 (apigenin, gallic acid, EGCG, quercetin), caspase-9 (apigenin, gallic acid, EGCG, quercetin), cytochrome c (gallic acid), Bax (apigenin, EGCG, quercetin), TRAIL (apigenin), and DR (apigenin), while the anti-apoptotic molecules that are downregulated are Bcl-2 (apigenin, gingerol, EGCG, and quercetin). Legend: FasL, Fas ligand; TNFα, tumor necrosis factor alpha; TRAIL, TNF-related apoptosis-inducing ligand; Fas, Fas receptor/ apoptosis antigen 1; TNFR, TNF receptor; DR, death receptor; FADD, Fas-associated death domain protein; Bcl-2, B-cell lymphoma type 2 protein; BH-3, Bcl-2 homology domain 3; Bid, BH3-interacting domain death agonist; Noxa, phorbol-12-myristate-13-acetate-induced protein 1; Bmf, Bcl-2 modifying factor; Puma, p53 upregulated modulator of apoptosis/ Bcl-2 binding component-3; Hkr, harakiri death protein; Bik, Bcl-2 interacting killer; Bad, Bcl-2 antagonist of cell death; Bax, Bcl-2-associated X protein; Bak, Bcl-2-antagonist/killer-1; ER, endoplasmic reticulum; upregulation (red ↑); downregulation (red ↓); schematic diagram was performed with Biomedical PPT Toolkit Suite, Motifolio, Inc., Ellicott Citty, MD, USA.

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