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Journal of Virology, September 2008, p. 8487-8499, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00851-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Targeting the Apoptotic Pathway with BCL-2 Inhibitors Sensitizes Primary Chronic Lymphocytic Leukemia Cells to Vesicular Stomatitis Virus-Induced Oncolysis{triangledown}

Vanessa Fonseca Tumilasci,1,2 Stephanie Olière,1,2,{dagger} Thi Lien-Ahn Nguyên,1,2,{dagger} April Shamy,3 John Bell,4 and John Hiscott1,2,3*

Molecular Oncology Group, Lady Davis Institute-Jewish General Hospital,1 Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3T 1E2, Canada,2 Department of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada,3 Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1Y 4E9, Canada4

Received 22 April 2008/ Accepted 17 June 2008

Chronic lymphocytic leukemia (CLL) is characterized by clonal accumulation of CD5+ CD19+ B lymphocytes that are arrested in the G0/G1 phase of the cell cycle and fail to undergo apoptosis because of overexpression of the antiapoptotic B-cell CLL/lymphoma 2 (BCL-2) protein. Oncolytic viruses, such as vesicular stomatitis virus (VSV), have emerged as potential anticancer agents that selectively target and kill malignant cells via the intrinsic mitochondrial pathway. Although primary CLL cells are largely resistant to VSV oncolysis, we postulated that targeting the apoptotic pathway via inhibition of BCL-2 may sensitize CLL cells to VSV oncolysis. In the present study, we examined the capacity of EM20-25—a small-molecule antagonist of the BCL-2 protein—to overcome CLL resistance to VSV oncolysis. We demonstrate a synergistic effect of the two agents in primary ex vivo CLL cells (combination index of 0.5; P < 0.0001). In a direct comparison of peripheral blood mononuclear cells from healthy volunteers with primary CLL, the two agents combined showed a therapeutic index of 19-fold; furthermore, the combination of VSV and EM20-25 increased apoptotic cell death in Karpas-422 and Granta-519 B-lymphoma cell lines (P < 0.005) via the intrinsic mitochondrial pathway. Mechanistically, EM20-25 blocked the ability of the BCL-2 protein to dimerize with proapoptotic BAX protein, thus sensitizing CLL to VSV oncolytic stress. Together, these data indicate that the use of BCL-2 inhibitors may improve VSV oncolysis in treatment-resistant hematological malignancies, such as CLL, with characterized defects in the apoptotic response.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, 3755 Cote Ste. Catherine, Montreal, Quebec, Canada H3T 1E2. Phone: (514) 340-8222, ext. 5265. Fax: (514) 340-7576. E-mail: john.hiscott{at}mcgill.ca

{triangledown} Published ahead of print on 25 June 2008.

{dagger} These two authors contributed equally to this work.

Journal of Virology, September 2008, p. 8487-8499, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00851-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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