Nutritional chemoprevention is particularly suitable for prostate cancer. Gnetin C, a resveratrol dimer found abundantly in the melinjo plant (Gnetum gnemon), may possess more potent biological properties compared to other stilbenes. We examined the effects of gnetin C in a high-risk premalignant transgenic mouse model overexpressing tumor-promoting metastasis-associated protein 1 (MTA1) on the background of Pten heterozygosity (R26MTA1; Pten+/f; Pb-Cre+). Mice were fed diets supplemented with the following compounds: pterostilbene (70 mg/kg diet); gnetin C, high dose (70 mg/kg diet); and gnetin C, low dose (35 mg/kg diet). Prostate tissues were isolated after 17 weeks and examined for histopathology and molecular markers. Serum was analyzed for cytokine expression. Gnetin C-supplemented diets substantially delayed the progression of preneoplastic lesions compared to other groups. Prostate tissues from gnetin C-fed mice showed favorable histopathology, with decreased severity and number of prostatic intraepithelial neoplasia (PIN) foci, reduced proliferation, and angiogenesis. A decreased level of MTA1, concurrent with the trend of increasing phosphatase and tensin homolog expression and reduced interleukin 2 (IL-2) levels in sera, were also detected in gnetin C-fed mice. Importantly, gnetin C did not exert any visible toxicity in mice. Our findings demonstrate that a gnetin C-supplemented diet effectively blocks MTA1-promoted tumor progression activity in high-risk premalignant prostate cancer, which indicates its potential as a novel form of nutritional interception for prostate cancer chemoprevention.

Prostate cancer is common among aging men. No cancer treatment is provided during active surveillance for prostate cancer. Targeted nutritional interception may prove to be the most appropriate chemoprevention for intermediate- and high-risk patients. Here, for the first time, we investigate the efficacy of Gnetin C, a resveratrol-dimer found abundantly in melinjo (Gnetum gnemon) plant that is characterized with improved pharmacokinetics compared to other stilbenes, in a transgenic mouse model of prostate cancer. We have generated two prostate-specific mouse models, one overexpressing MTA1 on the background of Pten heterozygosity (R26MTA1; Pten+/f), and the other overexpressing MTA1 on the background of Pten loss (R26MTA1; Ptenf/f). Chemoprevention design included Gnetin C- dietary supplementation in the high-risk model while the therapeutic design included i.p. administration in the more aggressive R26MTA1; Ptenf/f genotype. Our results show that while MTA1 cooperates with PTEN deficiency to accelerate PIN development by increasing MTA1-associated signaling, Gnetin C intervention combats the progression of prostate cancer. We show that mice treated with Gnetin C (7 mg/kg bw, daily i.p.) exhibited more favorable histopathology with decreased severity and number of PIN foci (41.23% reduction) accompanied by reduced proliferation (Ki67, 57.43% reduction), angiogenesis (CD31, 86.91% reduction), AR (31.57% reduction), and MTA1 (27.94% reduction). Ongoing chemopreventive studies with four different diets [Control-diet; Gnetin C high dose (70 mg/kg diet); Gnetin C low dose (35 mg/kg diet); and pterostilbene (70 mg/kg diet)] are in progress. Altogether, these data provide an evidence for efficacy of Gnetin C in blocking prostate cancer progression and reveal its potential for novel chemopreventive and therapeutic implications in prostate cancer.Supported by NCI/NIH R15CA216070 to ASL Citation Format: Gisella Campanelli, Rabab Al Deabel, Anand Puaar, Prashanth Parupathi, Amee Adhvaryu, Avinash Kumar, Anait S. Levenson. Gnetin C for chemoprevention and chemotherapy of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5945.