Quercetin-Resveratrol Combination for Prostate Cancer Management in TRAMP Mice.

Chandra K Singh,Imtiaz A Siddiqui,Charlotte A Mintie,Nihal Ahmad,Jennifer E Panackal,Mary A Ndiaye,Gagan Chhabra

doi:10.3390/cancers12082141

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.

Highlights

Prostate cancer (PCa) is the most frequently diagnosed cancer accounting for more than one in five new cancer diagnoses affecting men in the US [1]
Using the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice, a clinically relevant model for PCa biology and therapeutic studies, we determined if using a combination of quercetin and resveratrol would impart better anti-cancer effects than either agent alone
Our results show that quercetin and/or resveratrol treatments result in a decrease in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) levels, it appears that the protein is reduced in both quercetin and resveratrol alone treatments, in addition to the combination (Figure 6f)

Summary

Introduction

Prostate cancer (PCa) is the most frequently diagnosed cancer accounting for more than one in five new cancer diagnoses affecting men in the US [1]. PCa is generally slow-growing and follows a distinct progression pattern which makes it ideal for both prevention and intervention studies [2]. Even though therapies like surgery, endocrine therapy, or radiotherapy provide control over PCa progression, a considerable number of patients advance to a metastatic, hormone-refractory state. The identification of novel mechanism-based approaches is desired for the prevention and/or treatment of PCa. Historically, plant-based and dietary agents have been used medicinally in a variety of health conditions, including PCa [3,4]. The grape antioxidant resveratrol (chemically: 3,5,40 -trihydroxystilbene) is one such agent that is being extensively studied for its health-promoting effects.

Methods

Results

Conclusion