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

Abstract

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.

• Authors: Wenbo Zhu, Jingjie Li, Sihan Wu, Shifeng Li, Liang Le, Xingwen Su, Pengxin Qiu, Haiyan Hu, Guangmei Yan
• Journal: Pancreas (Pancreas) Vol. 41 Issue 7 Pg. 1029-38 (Oct 2012) ISSN: 1536-4828 [Electronic] United States
• PMID: 22617708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Antineoplastic Agents, Alkylating
• Diterpenes
• Epoxy Compounds
• HSP27 Heat-Shock Proteins
• Phenanthrenes
• RNA, Small Interfering
• Deoxycytidine
• triptolide
• Cisplatin
• Gemcitabine

Topics

• Animals
• Antimetabolites, Antineoplastic
• Antineoplastic Agents, Alkylating
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cisplatin (administration & dosage)
• Deoxycytidine (analogs & derivatives)
• Diterpenes (administration & dosage)
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm
• Drug Synergism
• Epoxy Compounds (administration & dosage)
• Female
• HSP27 Heat-Shock Proteins (antagonists & inhibitors, genetics)
• Humans
• Mice
• Mice, Nude
• Mitochondria (physiology)
• Neoplasm Transplantation
• Pancreatic Neoplasms (drug therapy, pathology)
• Phenanthrenes (administration & dosage)
• RNA, Small Interfering (genetics)
• Transfection
• Gemcitabine