Targeting the Apoptotic Pathway with BCL-2 Inhibitors Sensitizes Primary Chronic Lymphocytic Leukemia Cells to Vesicular Stomatitis Virus-Induced Oncolysis
| Autor: | Stephanie Oliere, Vanessa Tumilasci, April Shamy, John C. Bell, John Hiscott, Thi Lien-Nahn Nguyên |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Time Factors Chronic lymphocytic leukemia Drug Evaluation Preclinical Tetrazolium Salts Apoptosis Jurkat cells Jurkat Cells immune system diseases hemic and lymphatic diseases Cells Cultured Aged 80 and over Membrane Potential Mitochondrial Oncolytic Virotherapy Formazans Molecular Structure biology Middle Aged Virus-Cell Interactions Leukemia Proto-Oncogene Proteins c-bcl-2 Vesicular stomatitis virus Caspases Female Adult Cell Survival Immunology Antineoplastic Agents Microbiology Vesicular stomatitis Indiana virus CD19 Cell Line Tumor Virology medicine Humans Benzopyrans Aged medicine.disease biology.organism_classification Leukemia Lymphocytic Chronic B-Cell Oncolytic virus Case-Control Studies Insect Science Barbiturates Leukocytes Mononuclear biology.protein Cancer research CD5 |
| Zdroj: | Journal of Virology. 82:8487-8499 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.00851-08 |
| Popis: | Chronic lymphocytic leukemia (CLL) is characterized by clonal accumulation of CD5 + CD19 + B lymphocytes that are arrested in the G 0 /G 1 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. |
| Databáze: | OpenAIRE |
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