Journal
BLOOD
Volume 119, Issue 25, Pages 6089-6098Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-09-378141
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Funding
- Multiple Myeloma Research Foundation [CA63753, CA93738, CA100866]
- National Institutes of Health [RC2CA148431, P50CA130805]
- Leukemia & Lymphoma Society of America [R6181-10]
- Myeloma Specialized Program of Research Excellence (SPORE) award [CA142509]
- Lymphoma SPORE award [CA130805]
- The V Foundation
- Multiple Myeloma Research Foundation
- NIH-NINDS center core grant [5P30NS047463]
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Interactions between the multikinase inhibitor sorafenib and the BH3-mimetic obatoclax (GX15-070) were examined in human acute myeloid leukemia (AML) cells. Treatment with sorafenib/obatoclax induced pronounced apoptosis in and reduced the clonogenic growth of multiple AML lines and primary AML cells but not normal CD34(+) cells. Sorafenib triggered rapid and pronounced Mcl-1 down-regulation accompanied by enhanced binding of Bim to Bcl-2 and Bcl-xL, effects that were abolished by obatoclax coadministration. Notably, shRNA knockdown of Bim, Bak, or Bax, but not Noxa, significantly attenuated obatoclax/sorafenib lethality, whereas ectopic expression of Mcl-1 exerted a protective effect. Furthermore, exposure of leukemia cells to sorafenib and obatoclax markedly induced autophagy, reflected by rapid and pronounced LC3 processing and LC3-green fluorescent protein (GFP) punctate formation. Multiple autophagy inhibitors or VPS34 knockdown, significantly potentiated sorafenib/obatoclax lethality, indicating a cytoprotective role for autophagy in this setting. Finally, studies in a xenograft mouse model revealed that combined sorafenib/obatoclax treatment markedly reduced tumor growth and significantly prolonged survival in association with Mcl-1 down-regulation and apoptosis induction, whereas agents administered individually had only modest effects. These findings suggest that combining sorafenib with agents that inhibit Mcl-1 and Bcl-2/Bcl-xL such as obatoclax may represent a novel and potentially effective strategy in AML. (Blood. 2012; 119(25):6089-6098)
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