BCL-2 inhibitors sensitize therapy-resistant chronic lymphocytic leukemia cells to VSV oncolysis

Mol Ther. 2013 Jul;21(7):1413-23. doi: 10.1038/mt.2013.91. Epub 2013 May 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biphenyl Compounds / pharmacology
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Immunoprecipitation
  • Indoles
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy*
  • Mice
  • Nitrophenols / pharmacology
  • Oncolytic Viruses / genetics
  • Oncolytic Viruses / physiology*
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrroles / pharmacology
  • Sulfonamides / pharmacology
  • Vesicular stomatitis Indiana virus / genetics*
  • Vesicular stomatitis Indiana virus / physiology

Substances

  • ABT-737
  • Biphenyl Compounds
  • Indoles
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • Sulfonamides
  • obatoclax