Document Detail


VSV oncolysis in combination with the BCL-2 inhibitor obatoclax overcomes apoptosis resistance in chronic lymphocytic leukemia.
MedLine Citation:
PMID:  20842105     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In chronic lymphocytic leukemia (CLL), overexpression of antiapoptotic B-cell leukemia/lymphoma 2 (BCL-2) family members contributes to leukemogenesis by interfering with apoptosis; BCL-2 expression also impairs vesicular stomatitis virus (VSV)-mediated oncolysis of primary CLL cells. In the effort to reverse resistance to VSV-mediated oncolysis, we combined VSV with obatoclax (GX15-070)-a small-molecule BCL-2 inhibitor currently in phase 2 clinical trials-and examined the molecular mechanisms governing the in vitro and in vivo antitumor efficiency of combining the two agents. In combination with VSV, obatoclax synergistically induced cell death in primary CLL samples and reduced tumor growth in severe combined immunodeficient (SCID) mice-bearing A20 lymphoma tumors. Mechanistically, the combination stimulated the mitochondrial apoptotic pathway, as reflected by caspase-3 and -9 cleavage, cytochrome c release and BAX translocation. Combination treatment triggered the release of BAX from BCL-2 and myeloid cell leukemia-1 (MCL-1) from BAK, whereas VSV infection induced NOXA expression and increased the formation of a novel BAX-NOXA heterodimer. Finally, NOXA was identified as an important inducer of VSV-obatoclax driven apoptosis via knockdown and overexpression of NOXA. These studies offer insight into the synergy between small-molecule BCL-2 inhibitors such as obatoclax and VSV as a combination strategy to overcome apoptosis resistance in CLL.
Authors:
Sara Samuel; Vanessa F Tumilasci; Stephanie Oliere; Thi Liên-Anh Nguyên; April Shamy; John Bell; John Hiscott
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-14
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  18     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-01     Completed Date:  2011-04-18     Revised Date:  2013-05-27    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2094-103     Citation Subset:  IM    
Affiliation:
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology
Apoptosis
Cell Line, Tumor
Combined Modality Therapy
Disease Models, Animal
Female
Genetic Therapy
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / therapy*
Mice
Mice, SCID
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Pyrroles / pharmacology*
Reverse Transcriptase Polymerase Chain Reaction
Vesiculovirus* / physiology
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrroles; 0/obatoclax
Comments/Corrections

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