Tumor cells have devised several strategies to block the mitochondrial pathway of apoptosis despite endogenous or pharmacological cues to die. This process of cell death proceeds through the coordinated regulation of multiple anti-apoptotic and pro-apoptotic BCL-2 family proteins that ultimately impinge on the integrity of the outer mitochondrial membrane. Once compromised, mitochondria release pro-apoptotic factors to promote caspase activation and the apoptotic phenotype. Within the BCL-2 family exists a subclass of pro-apoptotic members termed the BH3-only proteins, which directly and/or indirectly functionally regulate the remaining anti- and pro-apoptotic BCL-2 proteins to compromise mitochondria and engage apoptosis. The focus of this review is to discuss the cellular and pharmacological regulation of the BH3-only proteins to gain a better understanding of the signaling pathways and agents that regulate this class of proteins. As the BH3-only proteins increase cellular sensitivity to pro-apoptotic agents such as chemotherapeutics, numerous small-molecule BH3 mimetics have been developed and are currently in various phases of clinical trials. Toward the end of the review, the discovery and application of the small-molecule BH3 mimetics will be discussed.
Keywords: BCL-2 family; BH3-only proteins; apoptosis; cancer; mitochondria.