Brucein D induces apoptosis in pancreatic adenocarcinoma cell line PANC-1 through the activation of p38-mitogen activated protein kinase

Pancreatic cancer is a malignant disease with extremely high mortality. Our previous work found that Brucea javanica fruit possesses potent anti-pancreatic cancer activity. In the present study, brucein D (BD), a quassinoid found abundantly in B. javanica fruit, was evaluated for its anti-proliferative and apoptogenic actions. BD inhibited the growth of three pancreatic cancer cell lines, i.e., PANC-1, SW1990 and CAPAN-1, but exerted only modest cytotoxicity on non-tumorigenic Hs68 cells. Hoechst 33342 staining and Cell Death Detection ELISA(PLUS) assay revealed that BD-induced DNA fragmentation in PANC-1 cells. Moreover, subG1 phase was observed in the BD-treated cells. Western blot experiments indicated that BD exposure augmented caspase 3, 8, 9 and bak protein levels, while attenuating the expression of bcl-2. Furthermore, BD treatment promoted phosphorylation of p38-MAPK. The selective p38-MAPK inhibitor SB203580 effectively mitigated the BD-induced apoptosis in PANC-1 cells, suggesting that p38-MAPK signaling pathway was involved in the BD-induced apoptosis in pancreatic cancer cells. Taken together, our results provide experimental evidence to support the traditional use of B. javanica fruit in cancer treatment, and render BD a promising chemical candidate for further development into anti-pancreatic cancer agent. (C) 2009 Elsevier Ireland Ltd. All rights reserved.