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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Departments of 1 Medicine, 2 Biochemistry, and 3 Pharmacology, Virginia Commonwealth University and Massey Cancer Center, Richmond, Virginia
Requests for reprints: Steven Grant, Division of Hematology/Oncology, Virginia Commonwealth University/Massey Cancer Center, MCV Station Box 230, Richmond, VA 23298. Phone: 804-828-5211; Fax: 804-828-2178; E-mail: stgrant{at}vcu.edu.
The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL but not Mcl-1, which may confer resistance to this novel agent. Here, we show that Mcl-1 down-regulation by the cyclin-dependent kinase (CDK) inhibitor roscovitine or Mcl-1-shRNA dramatically increases ABT-737 lethality in human leukemia cells. ABT-737 induces Bax conformational change but fails to activate Bak or trigger Bax translocation. Coadministration of roscovitine and ABT-737 untethers Bak from Mcl-1 and Bcl-xL, respectively, triggering Bak activation and Bax translocation. Studies employing Bax and/or Bak knockout mouse embryonic fibroblasts (MEFs) confirm that Bax is required for ABT-737 ± roscovitine lethality, whereas Bak is primarily involved in potentiation of ABT-737–induced apoptosis by Mcl-1 down-regulation. Ectopic Mcl-1 expression attenuates Bak activation and apoptosis by ABT-737 + roscovitine, whereas cells overexpressing Bcl-2 or Bcl-xL remain fully sensitive. Finally, Mcl-1 knockout MEFs are extremely sensitive to Bak conformational change and apoptosis induced by ABT-737, effects that are not potentiated by roscovitine. Collectively, these findings suggest down-regulation of Mcl-1 by either CDK inhibitors or genetic approaches dramatically potentiate ABT-737 lethality through cooperative interactions at two distinct levels: unleashing of Bak from both Bcl-xL and Mcl-1 and simultaneous induction of Bak activation and Bax translocation. These findings provide a mechanistic basis for simultaneously targeting Mcl-1 and Bcl-2/Bcl-xL in leukemia. [Cancer Res 2007;67(2):782–91]
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