Bcl-2 family: Translational aspects

The Bcl-2 family of antiapoptotic and proapoptotic proteins serve as key regulators of the mitochondrial pathway of apoptosis. Multiple signals from a variety of cell death stimuli converge upon mitochondria to trigger the intrinsic apoptotic cascade. Bcl-2 family proteins are intimately related to prognosis and therapeutic resistance in acute myeloid leukemia (AML), making them rational targets for drug development. Also, directly targeting Bcl-2 family proteins circumvents many of the problems associated with targeting upstream molecules. The Bcl-2 antisense oligonucleotide oblimersen failed to live up to its initial promise in large phase III trials. The discovery of ABT-737, a novel, small-molecule inhibitor of specific protein–protein interactions, gave a much-needed impetus to the field of “BH3 mimetic” research. The demonstration that Mcl-1, an antiapoptotic Bcl-2 family protein that is not inhibited by ABT-737 or its analogs, is of crucial importance in AML, underscores the need for rational drug combinations that simultaneously target multiple arms of the apoptotic regulatory machinery.