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Hum Gene Ther. 2018 Aug;29(8):950-961. doi: 10.1089/hum.2017.055. Epub 2017 Jul 27.

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

Tan Y1, Lin Y1,2, Li K1,3, Xiao X1,4, Liang J1, Cai J1, Guo L1, Li C1, Zhu W1, Xing F1, Mai J1, Gu J1, Tan X5, Yin W6, Lu B1, Qiu P1, Su X1, Gao M1, Hu J7, He S8, Lu L9, Gong S10, Yan G1, Zhang H1,11.

Author information

1
1 Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University , Guangzhou, China.
2
2 Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University , Guangzhou, China.
3
3 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
4
4 Department of Pharmacy, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
5
5 Intensive Care Unit, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China.
6
6 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University , Guangzhou, China.
7
7 Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University , Guangzhou, China.
8
8 Appel Alzheimer's Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York.
9
9 Pathology and Laboratory Medicine, University of Kansas Medical Center , Kansas City, Kansas.
10
10 Guangzhou Virotech Pharmaceutical Co., Ltd . Guangzhou, China .
11
11 Department of Nutrition, School of Public Health, Sun Yat-sen University , Guangzhou, China.

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.

KEYWORDS:

Bcl-xL inhibitor; combination therapy; oncolytic virus M1

PMID:
28750564
DOI:
10.1089/hum.2017.055

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