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: Sin Ting Lau, Zhi-Xiu Lin, Yonghong Liao, Ming Zhao, Christopher H K Cheng, Po Sing Leung
• Journal: Cancer letters (Cancer Lett) Vol. 281 Issue 1 Pg. 42-52 (Aug 18 2009) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 19286308 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Neoplasm Proteins
• Quassins
• bruceine D
• p38 Mitogen-Activated Protein Kinases
• Caspases
• Camptothecin

Topics

• Adenocarcinoma (pathology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Camptothecin (pharmacology)
• Caspases (physiology)
• Cell Division (drug effects)
• Cell Line, Tumor (cytology, drug effects)
• DNA Replication (drug effects)
• Enzyme Activation (drug effects)
• Fibroblasts (cytology, drug effects)
• Humans
• Neoplasm Proteins (antagonists & inhibitors, physiology)
• Pancreatic Neoplasms (pathology)
• Quassins (pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, physiology)