P-0094 Alpha-Mangostin Inhibits the Proliferation of Pancreatic Carcinoma Cells Via Apoptosis Induction and Cell Cycle Arrest

Abstract

IntroductionPancreatic carcinoma (PCa) is one of the few malignancies with nearly 100% mortality once diagnosed. There is a need to characterize promising dietary agents for chemoprevention and therapy of PCa. Anticarcinogenic properties of xanthones have been linked with an impressive amount of data from human cell culture and animal model systems. We examined the anticancer effect of alpha-mangostin, one xanthone-type compound derived from the tropical fruit Mangosteen, in human PCa cells and its role in targeting cell cycle-related proteins involved in PCa carcinogenesis. MethodsWe studied the effect of alpha-mangostin on apoptosis and cell cycle in human pancreatic cancer BxPC-3 and ASPC-1 cells by flow cytometry assay, and the effect on proliferation by colony formation assay. We evaluated alpha-mangostin for its ability to inhibit cyclins/cyclin-dependent kinases 4 (CDK4) via a cell free-based kinase assay. We assessed the effect of alpha-mangostin to inhibit proteins upstream of cell cycle and apoptosis using Western blot. Additionally, we studied the effects of alpha-mangostin combined with gemcitabine on cell cycle arrest. ResultsIn both BxPC-3 and ASPC-1 cells, treatment of alpha-mangostin results in a direct inhibition of the proliferation and significant arrest of cells at G1 phases of the cell cycle. We also found that alpha-mangostin significantly induced the induced early apoptosis in the both cells. A significant inhibition (P <0.01) was observed at cyclinD1/CDK4 with 10 µM alpha-mangostin. We observed a decrease in pro-caspase-3, an increase in the active form of caspase-3, an increase in p27 Kip1, and a decrease in cyclins D1 and D3 by western blot. Alpha-mangostin synergized the antiproliferative and pro-apoptotic effects induced by gemcitabine in both cells. ConclusionThe ability to inhibit PCa cells in vitro via apoptosis induction and cell cycle arrest suggests alpha-mangostin may be a novel agent for the management of PCa.