VSV Oncolysis in Combination With the BCL-2 Inhibitor Obatoclax Overcomes Apoptosis Resistance in Chronic Lymphocytic Leukemia

Autor: Stephanie Oliere, John C. Bell, Vanessa Tumilasci, John Hiscott, April Shamy, Thi Lien-Anh Nguyen, Sara Samuel
Rok vydání: 2010
Předmět:
Programmed cell death
Indoles
Chronic lymphocytic leukemia
Cell
Antineoplastic Agents
Apoptosis
Mice
SCID
Biology
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Line
Tumor
hemic and lymphatic diseases
Drug Discovery
Genetics
medicine
Animals
Humans
Pyrroles
Molecular Biology
030304 developmental biology
Pharmacology
0303 health sciences
Gene knockdown
Reverse Transcriptase Polymerase Chain Reaction
Genetic Therapy
Vesiculovirus
medicine.disease
biology.organism_classification
Combined Modality Therapy
Leukemia
Lymphocytic
Chronic
B-Cell
Virology
3. Good health
Disease Models
Animal
Leukemia
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
chemistry
Vesicular stomatitis virus
030220 oncology & carcinogenesis
Cancer research
Molecular Medicine
Original Article
Female
Obatoclax
Zdroj: Molecular Therapy. 18:2094-2103
ISSN: 1525-0016
DOI: 10.1038/mt.2010.188
Popis: 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.
Databáze: OpenAIRE
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