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Targeting Multiple Arms of the Apoptotic Regulatory Machinery

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, Medical College of Virginia, 1101 East Marshall Street, P.O. Box 980230, Richmond, VA 23298-0230. Phone: 804-828-5211; Fax: 804-225-3788; E-mail: stgrant{at}hsc.vcu.edu.

ABT-737 targets Bcl-2/Bcl-xL but not Mcl-1, which confers resistance to this novel agent. Here, we summarize recent findings indicating that Mcl-1 represents a critical determinant of ABT-737 sensitivity and resistance, and that Mcl-1 down-regulation by various pharmacologic agents or genetic approaches dramatically increases ABT-737 lethality in diverse malignant cell types. These findings also show that the multidomain proapoptotic proteins Bax and Bak play important functional roles in ABT-737–mediated apoptosis, and that Bak activation is essential in potentiation of ABT-737 lethality by agents that down-regulate Mcl-1. Collectively, these findings suggest a novel therapeutic strategy targeting multiple arms of the apoptotic machinery. [Cancer Res 2007;67(7):2908–11]

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