Triptolide cooperates with cisplatin to induce apoptosis in gemcitabine-resistant pancreatic cancer

OBJECTIVES: We aim to pharmacologically downregulate heat shock protein 27 (HSP27) through triptolide (TPL) to improve the drug sensitivity of pancreatic cancer to cisplatin (DDP). METHODS: In vitro, we assessed cell viability and apoptosis by the combination of TPL and DDP in gemcitabine-resistant human pancreatic carcinoma PANC-1 and MIA PaCa-2 cell lines and examined the effect of silencing HSP27 by a small interfering RNA on cytotoxicity induced by TPL or DDP. In vivo, we apply TPL with DDP in a xenograft model to test the synergic action. RESULTS: Triptolide cooperates with DDP to decrease cell viability and to induce apoptosis via the mitochondrial pathway, which is accompanied by a sharp decline in HSP27. Knocking down endogenous HSP27 can sensitize cancer cells to cytotoxicity with TPL or DDP, indicating the critical role of HSP27 down-regulation in the synergic effect. Meanwhile, TPL acts in synergy with DDP to cause tumor regression in vivo. CONCLUSIONS: The combined therapy of TPL and DDP triggers a synergic apoptosis via inhibiting HSP27 in human gemcitabine-resistant pancreatic carcinoma and has a strong potential to be developed into a new effective regimen for pancreatic cancer treatment. ABBREVIATIONS: TPL - triptolideDDP - cisplatinHSP27 - heat shock protein 27 kdHSP70 - heat shock protein 70 kdHSP90 - heat shock protein 90 kdsiRNA - small interfering RNAHSPs - heat shock proteinsMTT - 3-(45-dimethylthiaziazol-2-yl)- 25-diphenyl tetrazolium bromideOD - optical densityLDH - lactate dehydrogenaseTNF - tumor necrosis factorHSF-1 - heat shock factor 1