title: Bruceine D induces apoptosis in pancreatic adenocarcinoma cell line PANC-1 through the activation of p38-mitogen activated protein kinase.
abstract: 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.
authors.affiliation: Department of Physiology, The Chinese University of Hong Kong, Shatin, NT, SAR, China.
authors.forename: Sin Ting
authors.initials: ST
authors.lastname: Lau
authors.forename: Zhi-Xiu
authors.initials: ZX
authors.lastname: Lin
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Liao
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Christopher H K
authors.initials: CH
authors.lastname: Cheng
authors.forename: Po Sing
authors.initials: PS
authors.lastname: Leung
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology; D020169:Caspases / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D036702:Quassins / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D036702:Quassins; C030412:bruceine D; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D002166:Camptothecin