BCL-2 inhibitors sensitize therapy-resistant chronic lymphocytic leukemia cells to VSV oncolysis.
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Molecular therapy : the journal of the American Society of Gene Therapy
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Many primary cancers including chronic lymphocytic leukemia (CLL) are resistant to vesicular stomatitis virus (VSV)-induced oncolysis due to overexpression of the antiapoptotic and antiautophagic members of the B-cell lymphoma-2 (BCL-2) family. In the present study, we investigated the mechanisms of CLL cell death induced as a consequence of VSV infection in the presence of BCL-2 inhibitors, obatoclax, and ABT-737 in primary ex vivo CLL patient samples. Microarray analysis of primary CD19⁺ CD5⁺ CLL cells treated with obatoclax and VSV revealed changes in expression of genes regulating apoptosis, the mechanistic target of rapamycin (mTOR) pathway, and cellular metabolism. A combined therapeutic effect was observed for VSV and BCL-2 inhibitors in cells from untreated patients and from patients unresponsive to standard of care therapy. In addition, combination treatment induced several markers of autophagy--LC3-II accumulation, p62 degradation, and staining of autophagic vacuoles. Inhibition of early stage autophagy using 3-methyladenine (3-MA) led to increased apoptosis in CLL samples. Mechanistically, a combination of BCL-2 inhibitors and VSV disrupted inhibitory interactions of Beclin-1 with BCL-2 and myeloid cell leukemia-1 (MCL-1), thus biasing cells toward autophagy. We propose a mechanism in which changes in cellular metabolism, coupled with pharmacologic disruption of the BCL-2-Beclin-1 interactions, facilitate induction of apoptosis and autophagy to mediate the cytolytic effect of VSV.
Medical Specialties | Medicine and Health Sciences | Osteopathic Medicine and Osteopathy
Animals, Biphenyl Compounds, Blotting, Western, Cell Line, Tumor, Cell Survival, Cells, Cultured, Flow Cytometry, Fluorescent Antibody Technique, Humans, Immunoprecipitation, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, Nitrophenols, Oncolytic Viruses, Piperazines, Proto-Oncogene Proteins c-bcl-2, Pyrroles, Sulfonamides, Vesicular stomatitis Indiana virus
Samuel, Sara; Beljanski, Vladimir; Van Grevenynghe, Julien; Richards, Stephanie; Ben Yebdri, Fethia; He, Zhong; Nichols, Carmen; Belgnaoui, S Mehdi; Steel, Courtney; Goulet, Marie-Line; Shamy, April; Brown, Dawn; Abesada, Guillermo; Haddad, Elias K; and Hiscott, John, "BCL-2 inhibitors sensitize therapy-resistant chronic lymphocytic leukemia cells to VSV oncolysis." (2013). College of Osteopathic Medicine Faculty Articles. 1567.