Gnetin C Intercepts MTA1-Associated Neoplastic Progression in Prostate Cancer

SIMPLE SUMMARY: The incidence of prostate cancer is increasing because of the aging population. Evidence suggests that diets rich in bioactive polyphenols can reduce the incidence of prostate cancer. The aim of this work was to investigate the potential of gnetin C, a compound found in the melinjo plant and commonly used in Indonesian foods, to block prostate cancer progression. To this end, we evaluated the anticancer efficacy of gnetin C-supplemented diets in a unique and adequate high-risk premalignant prostate cancer transgenic mouse model. Our results indicate that a gnetin C-supplemented diet reduces the progression of prostate cancer by reducing the proliferation of cells, inflammation, and the formation of blood vessels. The finding that a gnetin C-supplemented diet effectively blocks tumor progression in a preclinical mouse model may be exploited to initiate chemoprevention trials for novel nutritional interception for untreated patients under active surveillance. ABSTRACT: 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 (R26(MTA1); 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.