Targeting the Bcl-2 family for cancer therapy

Abstract

Introduction: Programmed cell death is well-orchestrated process regulated by multiple pro-apoptotic and anti-apoptotic genes, particularly those of the Bcl-2 gene family. These genes are well documented in cancer with aberrant expression being strongly associated with resistance to chemotherapy and radiation.

Areas covered: This review focuses on the resistance induced by the Bcl-2 family of anti-apoptotic proteins and current therapeutic interventions currently in preclinical or clinical trials that target this pathway. Major resistance mechanisms that are regulated by Bcl-2 family proteins and potential strategies to circumvent resistance are also examined. Although antisense and gene therapy strategies are used to nullify Bcl-2 family proteins, recent approaches use small molecule inhibitors (SMIs) and peptides. Structural similarity of the Bcl-2 family of proteins greatly favors development of inhibitors that target the BH3 domain, called BH3 mimetics.

Expert opinion: Strategies to specifically identify and inhibit critical determinants that promote therapy resistance and tumor progression represent viable approaches for developing effective cancer therapies. From a clinical perspective, pretreatment with novel, potent Bcl-2 inhibitors either alone or in combination with conventional therapies hold significant promise for providing beneficial clinical outcomes. Identifying SMIs with broader and higher affinities for inhibiting all of the Bcl-2 pro-survival proteins will facilitate development of superior cancer therapies.

Figure 1. Three subfamilies of Bcl-2 related proteins

Family members sharing four bcl-2 homology (BH) domains are the multidomain proteins. These proteins share a common three-dimensional fold. Anti-apoptotic proteins are antagonists of BAX and BAK, in part by directly binding to them. BH-3 only proteins only have BH3 domain. They respond to stress and are natural antagonists of anti-apoptotic proteins.

Figure 2. Pathway to apoptosis following various cellular insults

Chemotherapy, radiation and other insults can initiate apoptosis through the mitochondrial intrinsic pathway. Pro-apoptotic proteins (BAD, BIM, BID) are activated and upon its activation mitochondria release cytochrome c into the cytosol. Cytochrome c binds with apoptotic protease activating factor-1 (APAF1) to activate initiator caspase-9 subsequently leading to apoptosis.