Abstract 5085: Molecular analysis of chemopreventive effects of grape antioxidants resveratrol and quercetin in transgenic adenocarcinoma of the mouse prostate
Authors: Singh Chandra K. , Ndiaye Mary A. , Chhabra Gagan , Mintie Charlotte A. , Ahmad Nihal 
Published: August 2019

Abstract
Prostate cancer (PCa) is one of the most frequently diagnosed cancers of the male population and current treatments are insufficient to fully manage this neoplasm. Therefore, identification of novel mechanism-based approaches are needed for PCa management. Earlier, we demonstrated that a combination of the grape antioxidants resveratrol and quercetin impart superior anti-proliferative responses in multiple human PCa cell lines, as well as a significant anti-tumor response in transgenic adenocarcinoma of the mouse prostate (TRAMP) (Cancer Res 75(15 Suppl):2801). The rationale of the study was based on the fact that i) both resveratrol and quercetin are naturally present in several plants ii) quercetin improves bioavailability of resveratrol by inhibiting its sulfation, and iii) separately, both agents have shown potential for management of PCa in previously published studies. This study extended our previous work and determined the mechanisms of chemopreventive effects of resveratrol-quercetin combination employing a mouse PCa RT² Profiler PCR array that profiles 84 key PCa-related genes. For this, we employed tumor tissues generated in a chemoprevention protocol where TRAMP mice were given AIN76A diet supplemented with resveratrol (600 mg/kg), quercetin (60 mg/kg), or a combination of both. PCR array analysis found significant modulation (≥2-fold) in 14, 15, and 10 genes in the quercetin, resveratrol, and combination groups, respectively. To explore the involved gene networks using Ingenuity Pathway Analysis (IPA), we selected total 22 genes with ≥2-fold change in any one group and ≥1.5-fold change in other group(s). IPA analysis identified that resveratrol-quercetin modulated genes supported the cumulative actions of increased apoptosis, as well as inhibition of cell viability/proliferation, hyperplasia, vasculogenesis, and angiogenesis. Further, IPA predicted inhibition of major PCa promoting upstream signaling molecules viz. Pi3k, Vegf, Csf2, Ca2+, and Pth. This PCR array also identified decreased levels of Igf1, Egfr, Egr3, and Il6, which are known to support PCa progression, as well as found increased levels of Nkx3-1, which is a tumor suppressor in PCa. Furthermore, IPA exploration identified a gene network where decreased Igf1 emerged as a central regulatory player, interacting with most of the resveratrol-quercetin modulated genes. Additionally, employing IHC, immunoblot, and RT-qPCR analyses, we found marked decrease in the levels of cell proliferation markers Ki67 and PCNA, oxidative stress biomarker 4-HNE, EMT marker vimentin, and prosurvival marker Bcl2. These results suggest that this natural combination of grape polyphenols may be useful as a chemopreventive regimen for PCa. Further detailed studies including clinical trials are needed to determine the translational significance of our findings.
Citation Format: Chandra K. Singh, Mary A. Ndiaye, Gagan Chhabra, Charlotte A. Mintie, Nihal Ahmad. Molecular analysis of chemopreventive effects of grape antioxidants resveratrol and quercetin in transgenic adenocarcinoma of the mouse prostate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5085.