Targeting multiple arms of the apoptotic regulatory machinery.
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.
Dai
Yun
Y
Department of Medicine, Virginia Commonwealth University and Massey Cancer Center, Richmond, Virginia, USA.
Grant
Steven
S
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C501332:ABT-737; C494772:BAK1 protein, human; C494826:BAX protein, human; D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein