Abstract A67: Dietary xanthones for prostate cancer chemoprevention: From fruit extract to structure activity relationship studies

Abstract

Abstract The purple 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, anit-microbial and anti-diabetic properties. The principle constituents isolated from the mangosteen fruit are the xanthones with well over 50 unique entities isolated to date. Here we report on the properties of dietary xanthones for cancer chemoprevention using prostate cancer (PCa) as a model disease. Using a mangosteen fruit extract (MFE) standardized to alpha-mangostin (40%) and three other xanthones a significant decrease in cell viability was observed against four different prostate cancer cell lines (LNCaP, CWR22, PC3, DU145). Next, using an athymic nude mouse model implanted with CWR22Rv1 cells we randomized mice to receive intraperitoneally the standardized mangosteen fruit extract (MFE) or placebo two times weekly with tumors measured twice weekly once tumors reached a volume of 200 mm3. At the conclusion of the study the treatment group had a significantly smaller tumor with an average tumor volume of (143 mm3) compared to the placebo group (1135 mm3) representing an 87.5% smaller tumor in the treatment group. To gain an understanding of the pharmacology we selected alpha-mangostin as the lead compound and evaluated alpha-mangostin against fifty different protein kinases deregulated in cancer with 11 unique kinase targets identified. The three kinases displaying the most inhibition by alpha-mangostin included cyclinD1/CDK4, cyclinA1/CDK2, and Mek1. Using two different cells lines (LNCaP and DU145) 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. 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 and CyclinA1/CDK2 using cell free biochemical assays and molecular modeling. Collectively these data indicate that alpha-mangostin could be a promising agent for PCa prevention. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A67.