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

phase of the cell cycle and fail to undergo apoptosis because of overex-pression of the antiapoptotic B-cell CLL/lymphoma 2 (BCL-2) protein. Oncolytic viruses, such as vesicularstomatitis virus (VSV), have emerged as potential anticancer agents that selectively target and kill malignantcells via the intrinsic mitochondrial pathway. Although primary CLL cells are largely resistant to VSVoncolysis, we postulated that targeting the apoptotic pathway via inhibition of BCL-2 may sensitize CLL cellsto VSV oncolysis. In the present study, we examined the capacity of EM20-25—a small-molecule antagonist ofthe BCL-2 protein—to overcome CLL resistance to VSV oncolysis. We demonstrate a synergistic effect of thetwo agents in primary ex vivo CLL cells (combination index of 0.5;