Abstract 2582: Gnetin C inhibits reactivated AR signaling in advanced prostate cancer

The activation of androgen receptor (AR) is a key process in the development and progression of prostate cancer (PCa). After significant clinical response to androgen-deprivation therapy, patients with advanced PCa regularly relapse with more aggressive castrate-resistant PCa, in which AR and its oncogenic variants are reactivated. Therefore, there is an urgent necessity to develop therapeutic strategies that effectively suppress the tumor promoting signals associated with AR action in castrate-resistant PCa. Dietary stilbenes found in grapes and various berries are promising anticancer agents with multiple cellular targets, including AR. Particularly, we previously demonstrated that resveratrol (Res) and its naturally occurring analogs, pterostilbene and piceatannol, can decrease expression of AR in LNCaP and 22Rv1 cells, therefore presenting an attractive potential for stilbenes as promising pharmacologically safe agents in managing PCa. Gnetin C, a Res-dimer found abundantly in melinjo (Gnetum gnemon) plant, which possesses potent biological properties compared to Res and analogs due to its improved pharmacokinetics, is shown to be safe in healthy volunteers. Here, for the first time, we examine the efficacy of Gnetin C in targeting both full-length and ligand-independent AR splice variant (AR-V7) expressed in the castrate-resistant 22Rv1 cells. First, we found that Gnetin C shows significantly more potent cytotoxic effect in 22Rv1 cells compared to Res and Pter. Immunoblot analysis demonstrated that Gnetin C inhibited expression of both full-length (100 kDA) and truncated (80 kDA) AR-V7 in a dose-dependent manner and, importantly, with significantly higher efficacy than Res and Pter when treated with the same dose (50 μM). In addition, Gnetin C used in twice lesser dose (25 μM), showed substantially more inhibitory effect compared to flutamide and enzalutamide (50 μM), two known AR antagonists used in clinic. Moreover, since neuroendocrine trans-differentiation (NED) is associated with AR-dependent mechanisms and enzalutamide resistance in PCa, we evaluated the effects of Gnetin C on SYP and CHGA. Ongoing in vivo studies using transgenic mice with activated AR signaling treated with Gnetin C are in progress. Taken together, we propose that Gnetin C is a lead compound among stilbenes for effectively blocking AR reactivation in PCa and may potentially have noteworthy therapeutic implications against advanced PCa. Citation Format: Rabab M. Al Deabel, Joyce Zhang, Anand Puaar, Avinash Kumar, Anait S. Levenson. Gnetin C inhibits reactivated AR signaling in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2582.