Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation.

Abstract

PURPOSE:

Understanding the roles of mammalian autophagy in cancer highlights recent advances in the pharmacologic manipulation of autophagic pathways as a therapeutic strategy for cancer. However, autophagy status and corresponding functions in hepatocellular carcinoma (HCC) after therapeutic stress remain to be clarified. This study was to determine whether the autophagic machinery could be activated after chemotherapy and the contribution of autophagy to tolerance of oxaliplatin in HCC.

EXPERIMENTAL DESIGN:

Autophagy activation and cell death induced by oxaliplatin were examined in two HCC cell lines as well as in vivo using an HCC model in nude mice. HCC tissue samples with or without locoregional chemotherapy before surgery were also examined by immunohistochemical and electron microscopic analysis.

RESULTS:

Autophagy was functionally activated in HCC cell lines and xenografts after oxaliplatin treatment. Suppression of autophagy using either pharmacologic inhibitors or RNA interference of essential autophagy gene enhanced cell death induced by oxaliplatin in HCC cells. Generation of reactive oxygen species has an important role in the induction of cell death by oxaliplatin in combination with autophagy inhibitors. Critically, the combination of oxaliplatin with autophagy inhibitor chloroquine resulted in a more pronounced tumor suppression in HCC xenografts. Furthermore, autophagy-specific protein LC3 and autophagic autophagosome formation were induced to a significantly higher level in HCC specimens that had been subjected to locoregional chemotherapy.

CONCLUSIONS:

Autophagy activation under therapy stress contributes to HCC tumor cell survival. Targeting the autophagy pathway is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in HCC patients.

• Authors: Zhen-Bin Ding, Bo Hui, Ying-Hong Shi, Jian Zhou, Yuan-Fei Peng, Cheng-Yu Gu, Hua Yang, Guo-Ming Shi, Ai-Wu Ke, Xiao-Ying Wang, Kang Song, Zhi Dai, Ying-Hao Shen, Jia Fan
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 19 Pg. 6229-38 (Oct 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21825039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR

Chemical References

• Antimalarials
• Antineoplastic Agents
• Organoplatinum Compounds
• Reactive Oxygen Species
• Oxaliplatin
• Chloroquine

Topics

• Animals
• Antimalarials (pharmacology)
• Antineoplastic Agents (therapeutic use)
• Autophagy (drug effects, genetics, physiology)
• Carcinoma, Hepatocellular (drug therapy, physiopathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chloroquine (pharmacology)
• Drug Resistance, Neoplasm
• Humans
• Liver Neoplasms (drug therapy, physiopathology)
• Male
• Mice
• Mice, Nude
• Organoplatinum Compounds (therapeutic use)
• Oxaliplatin
• RNA Interference
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays