Table 3. Nutraceuticals and Epigenetic: some of the main evidence in prostate cancer cells.
| Nutraceuticals | Cellular Effects | Epigenetic Effects | Refs. | ||
|---|---|---|---|---|---|
| GENISTEIN | -Inhibition of PCa cell proliferation and invasion. -Decreased risk of PCa. -Reduced PSA. -Reduced tumor volume. -Antioxidant properties. -Inhibitory effect on NF- 𝜅B and Akt signalling pathways -Antagonizes estrogen and androgen-mediated signalling. -Suppresses the expression of the androgen receptor. -Inhibition of cell motility and invasiveness via miR-151a-5p modulation (PC-3 cell line). -Decreases the expression level of the minichromosome maintenance MCM2 gene (PC-3 cell line). -Up-regulation of Aplysia Ras Homology member I levels by down regulating miR-221 and miR-222 levels (PC-3 cell line). -Repressive effects on tripartite motif containing 68 (TRIM68) and phosphoglycerate kinase 1 (PGK1) protein expression (LNCaP, VCaP, PC-3, C4–2B and ARCaPM cell lines). |
-Demethylation or histone modification of miR genes (in PC-3, LNCaP, VCaP, C4-2B, ARCaPM and DU145 cell lines). -Inhibition of DMNT-1. -Up-regulation of mRNA expression of some tumor suppressor genes including GSTP1 and EPH through DNA demethylation and modulation of MDM2, Akt and NF-kB activity (in PC-3, LNCaP, DU145 cell lines). -Changes in histone H3K9 acetylation in the promoter region of Wnt antagonist genes (in ARCaP-E/ARCaP-M cell lines). -Up-regulation of miR-145 (PC-3 cell line). -Promoter demethylation of miR-29a and miR-1256 (in LNCaP, VCaP, PC-3, C4-2B and ARCaPM cell lines). -DNA methylation or histone modifications on miR-1260b promoter (in PC-3 and DU145 cell lines). |
[16, 99, 104, 105, 109,110, 111,112, 113,115, 117,161] |
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| RESVERATROL | -Decreases the risk of PCa. - Suppresses the expression of the androgen receptor. -Down-regulates the expression of the metastasis-associated antigen 1 (MAT1) protein. - Inhibition of ERK-1/2 and Akt and IGF-1 (PC-3M-MM2 cell line). - Restoration of Sirt1- S6K function and autophagy control (PCa tissue). - Up-regulation of programmed cell death 4-neoplastic transformation inhibitor and Maspin tumor suppressors (PC-3M-MM2 cell lines). |
-Modulation of Histone decetylation activity. -Activator of sirtuins and DNMT 3b inhibitor. -Up –and/or- down-regulation of miRNAs clusters (down-regulation of: miR-17, miR-18, miR-20a, miR-20b,miR-92b, miR-106a and miR-106b, miR-7, miR-1260, miR-1267, let-7c; up-regulation of: miR-654-5p, miR-150, miR-149, and miR-152, in DU145 and PC-3 cell lines). -Destabilization of MAT1/HDAC1 subunit with consequent p53 acetylation and apoptosis (in DU145 and LNCaP cell lines). |
[116,118, 119,120, 163,164] |
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|
CURCUMIN AND CURCUMIN-DERIVED ANALOGUES (CDF AND EF24) |
-Antioxidant and anti-inflammatory activities, increases the glutathione level and inhibits oxidant and cytokine-induced NF-αB activation and cytokines release. -Inhibition of cell proliferation, invasion, migration, angiogenesis, and inflammation. -Induces cell cycle arrest and apoptosis. -Decreases nuclear β-catenin and TCF4 and hence inhibits β-catenin /TCF signalling. -Down-regulates AR signal transductions. -Down-regulation of Akt, NF-κB pathways. - Inhibition of VEGF and IL-6 expression in hypoxic microenvironment (PC-3 and LNCaP cell lines). |
-Modulation of HDAC1,3,8 and DNMT1 activities. -De-methylation of the Nrf2 gene (in TRAMP-C1 mice). -Modulation of miR-15a, miR-16, miR-21, miR-22, miR-26, miR-101, miR-146, miR-200, miR-203, and let-7 in many cancer type (with possible targeting in PCa cells). -EF24: reduces the expression level of the oncogenic miR-21, and enhances the levels of PTEN and PDCD4 (in DU145 cell line). |
[122,123, 124,125, 126,127, 128,129, 130,162] |
||
| GREEN TEA EXTRACTS (EGCG) | -Antagonizes androgen action. -Inhibition of prostate cancer development and of distant site metastasis. -Inhibition of vascular endothelial growth factor A, matrix metalloproteinase-2 and -9, and insulin growth factor (IGF)-1 signalling (in TRAMP mice). |
-Down-regulation of AR acetylation and induction of AR protein translocation from the cytoplasmic compartment to nucleus (in Xenograft mouse model of PCa; LNCaP cell line). -Anti-histone acetyltransferase activity (in LNCaP, 22Rv1 and C4-2 cell lines). -AR antagonism and consequent up-regulation of miR-330 and down-regulation of miR-21 (in Xenograft mouse model of PCa). - Decreased expression of the oncomiRs (miR-92, miR-93, and miR-106b) and increased expression of the tumor suppressor miRs (miR-7-1, miR-34a, and miR-99a) leading to induction of extrinsic and intrinsic pathways of apoptosis (in several cancer types, and possibly in PCa cells). |
[132,133, 143,165, 166,167] |
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| I3C AND DIM | -Modulation of estrogen metabolism and down-regulation of PSA expression. -Inhibition of cell growth and induction of G1 cell-cycle arrest (in PC-3 cell line). - Induction of apoptosis by up-regulation of BAX, and down-regulation of BCL-2 and BCLXL, and inactivation of Akt and NF-kB (in LNCaP cell line). |
-Reduced expression of EZH2- histone methyltransferase, via modulation of let-7 targeting in EZH2 gene (PCa tissue). DIM: up-regulation of miR-200b, miR-200c and let-7 miRNA family members (cancer stem cells). |
[147-149] | ||
| ISOTHIOCYANATES AND SULFORAPHANE | -Inhibition of DHT-stimulated AR transcriptional activity -Anti-proliferative effects |
-Direct inhibition of DNA methylation, acting on DNMT1, or decreasing the acetylation of histones, by depletion of HDAC3 (in LNCaP cell line). PEITC: Modulation of miRNA targeting on p300/CBP-associated factor (PCAF). -Inhibition of dihydrotestosterone (DHT)-stimulated AR transcriptional activity. -Restoration of the normal histone deacetylase activity via miR-17 transactivation (in LNCaP cell line). -SULFORAPHANE: Demethylation of cyclin D2 promoter (in LNCaP cell line). |
[152,153, 154] |
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List of abbreviations: PCa: Prostate cancer; PSA, Prostate specific antigen; DNMT-1, DNA (cytosine-5-)-methyltransferase-1; GSTP-1, Glutathione S-transferase Pi 1 gene; EPH2, Ephrin receptor subfamily of the protein-tyrosine kinase family; MDM2, Mouse double minute 2 homolog; NF-kB, Nuclear factor k-B; AKT, Protein kinase B (PKB); H3K9, Histone H3 lysine 9 methylation; MAT1, metastasis associated 1 protein; Maspin, mammary serine protease inhibitor, belonging to serpin protein superfamily; S6K, ribosomal protein S6 kinase; TCF4, Transcription factor 4; Nrf2, Nuclear factor erythroid 2 [NF-E2]-related factor 2; p300/CBP, p300 and CREB binding protein (CBP); PCAF, p300/CBP-associated factor or K(lysine) acetyltransferase 2B; IGF-1, Insulin growth factor-1; CDF, Difluorinated-Curcumin; EF24 (diphenyl difluoroketone); PTEN, Phosphatase and tensin homolog protein; PDCD4, Programmed cell death protein 4; AR, Androgen receptor; EGCG, Epigallocatechin-3-gallate; I3C, Indole-3-Carbinol; DIM, 3,3’- Diindolylmethane; BAX, BCL2-Associated X Protein; Bcl-2, B-cell lymphoma 2 protein; BCLXL, B-cell lymphoma-extra large protein; EZH2, Enhancer of zeste homolog 2; DHT, Diidrotestosterone; HDAC-3, Histone deacetylases-3; PEITC, Glucosinolate-derived phenethyl isothiocyanate.