Journal article
BCL-2 inhibitors sensitize therapy-resistant chronic lymphocytic leukemia cells to VSV oncolysis
Molecular therapy, v 21(7), pp 1413-1423
Jul 2013
PMID: 23689597
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- BCL-2 inhibitors sensitize therapy-resistant chronic lymphocytic leukemia cells to VSV oncolysis
- Creators
- Sara Samuel - Jewish General HospitalVladimir Beljanski - Vaccine & Gene Therapy Institute of FloridaJulien Van Grevenynghe - Jewish General HospitalStephanie Richards - Vaccine & Gene Therapy Institute of FloridaFethia Ben Yebdri - Jewish General HospitalZhong He - Vaccine & Gene Therapy Institute of FloridaCarmen Nichols - Vaccine & Gene Therapy Institute of FloridaS Mehdi Belgnaoui - Jewish General HospitalCourtney Steel - Vaccine & Gene Therapy Institute of FloridaMarie-Line Goulet - Jewish General HospitalApril Shamy - Jewish General HospitalDawn Brown - Martin Health SystemGuillermo Abesada - Martin Health SystemElias K HaddadJohn Hiscott - Vaccine & Gene Therapy Institute of Florida
- Publication Details
- Molecular therapy, v 21(7), pp 1413-1423
- Publisher
- Springer Nature
- Grant note
- R21 CA192185 / NCI NIH HHS MOP 42562 / Canadian Institutes of Health Research
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine; Infectious Diseases (and HIV Medicine); Drexel University
- Web of Science ID
- WOS:000321112500015
- Scopus ID
- 2-s2.0-84879689538
- Other Identifier
- 991020099992504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental