Selective Antagonism of Bcl-xL Potentiates M1 Oncolysis by Enhancing Mitochondrial Apoptosis.

Abstract

Oncolytic virotherapy is a novel and intriguing treatment strategy for cancer therapy. However, the clinical potential of oncolytic virus as single agent is limited. M1 virus is a promising oncolytic virus that has been tested in preclinical studies. In this study, we investigated the effect of the combination use of M1 virus and Bcl-2 family inhibitors. A chemical compounds screening including ten Bcl-2 family inhibitors demonstrated that pan-Bcl-2 inhibitors selectively augmented M1 virus oncolysis in cancer cells at very low doses. The mechanism of the enhanced antitumor effect of pan-Bcl-2 inhibitors with M1 virus is mainly due to the inhibition of Bcl-xL, which synergizes with M1-induced upregulation of Bak to trigger apoptosis. In xenograft mouse models and patient-derived tumor tissues, the combination of M1 and pan-Bcl-2 inhibitors significantly inhibited tumor growth and prolonged survival, suggesting the potential therapeutic value of this strategy. These findings offer insights into the synergy between Bcl-xL inhibition and oncolytic virus M1 as a combination anticancer treatment modality.

• Authors: Yaqian Tan, Yuan Lin, Kai Li, Xiao Xiao, Jiankai Liang, Jing Cai, Li Guo, Chuntao Li, Wenbo Zhu, Fan Xing, Jialuo Mai, Jiayu Gu, Xiaohong Tan, Wei Yin, Bingzheng Lu, Pengxin Qiu, Xingwen Su, Mingshi Gao, Jun Hu, Songmin He, Ling Lu, Shoufang Gong, Guangmei Yan, Haipeng Zhang
• Journal: Human gene therapy (Hum Gene Ther) Vol. 29 Issue 8 Pg. 950-961 (08 2018) ISSN: 1557-7422 [Electronic] United States
• PMID: 28750564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-bcl-2

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Combined Modality Therapy
• Humans
• Mice
• Mitochondria (drug effects)
• Neoplasms (drug therapy, genetics, virology)
• Oncolytic Virotherapy (methods)
• Oncolytic Viruses (drug effects, genetics)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, genetics)
• Xenograft Model Antitumor Assays