Abstract
Prostate Cancer (PCa) is a leading cause of cancer-related morbidity and mortality in men. Therefore, novel mechanistically-driven approaches are needed for PCa management. Here, we determined the effects of grape antioxidants quercetin and/or resveratrol (60 and 600 mg/kg, respectively, in diet) against PCa in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP)-model in prevention and intervention settings. We found resveratrol alone and in combination significantly inhibited prostate tumorigenesis in prevention setting, while the same was seen only in combination after intervention. The observed effects were associated with marked inhibition in proliferation, oxidative stress, and tumor survival markers, and induced apoptosis markers. Utilizing PCa PCR array analysis with prevention tumor tissues, we identified that quercetin-resveratrol modulates genes involved in promoter methylation, cell cycle, apoptosis, fatty acid metabolism, transcription factors, androgen response, PI3K/AKT and PTEN signaling. Ingenuity Pathway Analysis (IPA) identified IGF1 and BCL2 as central players in two gene networks. Functional annotation predicted increased apoptosis and inhibited cell viability/proliferation, hyperplasia, vasculogenesis, and angiogenesis with dual treatment. Furthermore, IPA predicted upstream inhibition of major PCa signaling VEGF, Ca2+, PI3K, CSF2, PTH). Based on PCR array, we identified decreased levels of EGFR, EGR3, and IL6, and increased levels of IGFBP7 and NKX3.1, overall supporting anti-PCa effects of quercetin-resveratrol.
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