Abstract 2574: Mangosteen fruit extract promotes endoplasmic reticulum stress through upregulation of CHOP/GADD153 in prostate cancer cells

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: The mangosteen fruit (Garcinia mangostana) is native to Southeast Asia and has been reported to contain a variety of health promoting properties that include antioxidant, anti-inflammatory, anti-microbial and anti-diabetic activities. The principle constituents isolated from the mangosteen fruit are the xanthones with over 50 unique entities isolated to date. Prostate cancer (PCa) is the second most common cancer-related death in adult males and is ideal for evaluating promising cancer preventive agents because it develops at old age and is usually asymptomatic until advanced. This suggests that even a slight delay in the diagnosis of prostate cancer could have a profound public health impact. In our current study, we investigated the anticancer effects of a highly characterized mangosteen fruit extract on PCa cell lines to understand the mechanism of endoplasmic reticulum stress. Next, we evaluated the anticancer activity of mangosteen fruit extract in an athymic nude mouse model. Methods: Two human prostate cancer cell lines, 22Rv1 and LNCaP, were treated with a standardized mangosteen fruit extract. Flow cytometry, MTT, BrdU, and siRNA were used to evaluate cell apoptosis, cell viability and cell proliferation. Whole cell lysates were used to detect protein expression changes of androgen receptor (AR), pro-apoptotic protein Bax and other proteins involved in cell cycle or ER stress following treatment with mangosteen fruit extract. Next, we evaluated mangosteen fruit extract for anti-cancer activity in Athymic (nu/nu) nude mice inoculated with 22Rv1 cells. These mice received either mangosteen fruit extract or vehicle. In addition, a pharmacokinetics assay of mangosteen fruit extract, complete blood count (CBC), and serum biochemistry were performed on wild type C57BL6 mice for possible toxicity. Results: Our results demonstrate that mangosteen fruit extract effectively induced apoptosis, decreased cell viability and inhibited cell proliferation in multiple prostate cancer cell lines. Mangosteen fruit extract treatment induced a dose-dependent AR down-regulation and Bax up-regulation, induced G1 cell cycle arrest, and significantly increased the expression of ER stress proteins, such as PERK, CHOP and IRE1 in PCa cells. In addition, mangosteen fruit extract treatment significantly suppressed tumor growth in a xenograft tumor model and did not alter body weight, complete blood count or serum biochemistry in normal mice. Conclusion: Our results demonstrate that mangosteen fruit extract upregulated the ER stress proteins CHOP, PERK and IRE1. Mangosteen fruit extract treatment effectively suppressed PCa cell growth in a xenograft mouse model without obvious toxicity, suggesting further research is needed to determine its potential as a cancer preventive and/or therapeutic agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2574. doi:1538-7445.AM2012-2574