The angosteen fruit (Garcinia mangostana) is native to southeast Asia and has been receiving increased attention for its health promoting properties that include antioxidant, anti-inflammatory, anit-microbial and anti-diabetic properties. The principle constituents isolated from the mangosteen fruit are the xanthones with alpha-mangostin being the most abundant. Here we report on the properties of dietary xanthones for cancer chemoprevention using prostate cancer (PCa) as a model disease. In a separate abstract we provide promising results suggesting that a standardized mangosteen fruit extract promotes cell cycle arrest and decreases tumor formation in an athymic nude mouse model. To gain an understanding of the pharmacology of xanthones in cancer inhibition we selected alpha-mangostin as the lead compound and evaluated it against fifty different protein kinases deregulated in cancer in a cell free kinase assay. A kinase that is often deregulated in a variety of cancers including prostate is cyclinD1/CDK4 where alpha-mangostin was found to significantly inhibit the activity. Using two different cells lines (PC3 and CWR22) we have evidence suggesting alpha-mangostin promoted G1 cell cycle arrest by flow cytometry and western blot analysis of cyclins and CDKs with observed effects in the range of 5-10 μM. Further confirmatory studies were performed by western blot analysis. A preliminary pharmacokinetic analysis of mice administered 1 mg of alpha-mangostin intraperitoneally resulted in a plasma concentration of 7.3 μM - within the concentration of in vitro mechanistic studies. Next, using an athymic nude mouse model implanted with CWR22Rv1 cells we randomized mice to receive intraperitoneally the alpha-mangostin (>95%) or placebo two times weekly with tumors measured twice weekly. At the conclusion of the study the treatment group had a significantly smaller tumor with an average tumor volume of (400 mm3) compared to the placebo group (1225 mm3) representing a 69% smaller tumor in the treatment group. Based on these promising results we used purified xanthones from the mangosteen fruit and selected 9 xanthones for structure activity relationship studies against cyclinD1/CDK4 using cell free biochemical assays and molecular modeling. Collectively these data indicate that the purified xanthone alpha-mangostin could be a promising agent for PCa prevention.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2887.

©2010 American Association for Cancer Research
2010