title: BCL-2 inhibitors sensitize therapy-resistant chronic lymphocytic leukemia cells to VSV oncolysis.
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.
authors.affiliation: Lady Davis Institute-Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Samuel
authors.forename: Vladimir
authors.initials: V
authors.lastname: Beljanski
authors.forename: Julien
authors.initials: J
authors.lastname: Van Grevenynghe
authors.forename: Stephanie
authors.initials: S
authors.lastname: Richards
authors.forename: Fethia
authors.initials: F
authors.lastname: Ben Yebdri
authors.forename: Zhong
authors.initials: Z
authors.lastname: He
authors.forename: Carmen
authors.initials: C
authors.lastname: Nichols
authors.forename: S Mehdi
authors.initials: SM
authors.lastname: Belgnaoui
authors.forename: Courtney
authors.initials: C
authors.lastname: Steel
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Goulet
authors.forename: April
authors.initials: A
authors.lastname: Shamy
authors.forename: Dawn
authors.initials: D
authors.lastname: Brown
authors.forename: Guillermo
authors.initials: G
authors.lastname: Abesada
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D007211:Indoles; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D009596:Nitrophenols / Q000494:pharmacology; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics* / Q000502:physiology
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D007211:Indoles; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D013449:Sulfonamides; C520962:obatoclax