Abstract 4643: Effect of resveratrol-zinc combination on prostate tumor growth in transgenic adenocarcinoma of mouse prostate (TRAMP) model

Abstract

Abstract Prostate cancer (PCa) is a major cancer of males globally and is associated with significant mortality and morbidity across the globe. The trace element zinc (Zn) plays a critical role in a variety of prostatic functions and normal prostate accumulates Zn at up to ten-fold higher concentration than other soft tissues in the body. However, the cancerous prostate lose the ability to accumulate Zn and lower levels of prostatic Zn has been associated with development and progression of PCa. Studies have suggested that a dysregulation in the transport machinery of Zn, possibly mediated via ZIP and ZnT families of Zn transporters, may be associated with this neoplastic transformation of prostate. Thus, re-tuning of Zn transport machinery via pharmacological means could be useful in PCa management. We have previously demonstrated that the grape antioxidant resveratrol (RSV) enhances the anti-proliferative response of Zn by increasing Zn-transporter protein ZIP1 in prostate cancer cells in vitro (Cancer Res 2012; 72(8 Suppl): Abstract nr 3729. doi: 1538-7445.AM2012-3729). Here, we extended our study to determine the in vivo relevance of our in vitro findings. We assessed the effect of RSV (600 mg/kg in diet) in combination with Zn (15 and 30 ppm ZnSO4.7H2O in drinking water) against prostate cancer progression in TRAMP mice, employing two experimental protocols, which represent prevention and intervention settings, respectively. We found that RSV-Zn combination, when given prior to tumor initiation (4 weeks of age), showed superior anti-tumor efficacy than either of the agents alone. However, we did not find a significant anti-tumor response of RSV and/or Zn in the intervention protocol. We also determined the effect of RSV and/or treatments on markers of proliferation and apoptosis in tumor tissues obtained from TRAMP mice. Interestingly, we found that lower dose of Zn (15 ppm) was most consistent in imparting anti-proliferative response; resulting in a significant i) decrease in tumor weight/volume, ii) decrease in proliferative marker PCNA, iii) increase of pro-apoptotic Bax, and iv) decrease of the pro-survival Bcl2. In addition, the observed response of RSV-Zn combination was associated with an increase in ZIP4 protein. Further experiments are ongoing to dissect the mechanism of the PCa chemoprevention effects of RSV-Zn combination. Outcome of this study may provide a foundation for the use of RSV-Zn combination for PCa management. Citation Format: Chandra K. Singh, Minakshi Nihal, Jasmine George, Imtiaz A. Siddiqui, Hasan Mukhtar, Nihal Ahmad. Effect of resveratrol-zinc combination on prostate tumor growth in transgenic adenocarcinoma of mouse prostate (TRAMP) model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4643. doi:10.1158/1538-7445.AM2015-4643