Recent advances in the development of anticancer agents targeting cell death inhibitors in the Bcl-2 protein family

Hematopoietic malignancies frequently are characterized by defects in apoptosis signaling. This renders the malignant cells resistant to endogenous apoptotic stimuli, as well as exogenous stimuli, such as chemotherapy drugs and radiation. The defective apoptosis seen in human cancers often results from overexpression of antiapoptotic proteins in the Bcl-2 protein family, particularly Bcl-2 and Bcl-X-L. A great deal of effort is currently aimed at developing novel agents to inhibit the expression or function of these proteins. Antisense agents directed against Bcl-2 mRNA are showing considerable promise in clinical trials. In addition, detailed knowledge of the structures of Bcl-2 and Bcl-X-L, coupled with high-throughput and computer-assisted screening of chemical libraries, has led to the identification of a number of short peptides and small organic molecules capable of inhibiting Bcl-2 and Bcl-X-L function. These newly described agents hold considerable promise for enhancing the chemo- and radiation sensitivities of Bcl-2- and Bcl-X-L-overexpressing cancers. This review will highlight recent advances in the development and testing of agents targeting cell death inhibitors in the Bcl-2 protein family.