Apoptosis, especially the intrinsic mitochondrial cell death pathway, is regulated by the BCL-2 family of proteins. Defects in apoptotic machinery are one of the main mechanisms that cells employ to evade cell death and become cancerous. Targeting the apoptotic defects, either by direct inhibition of BCL-2 family proteins or through modulation of regulatory pathways, can restore cell sensitivity to cell death. This review will focus on the aspects of BCL-2 family proteins, their interactions with kinase pathways, and how novel targeted agents can help overcome the apoptotic blockades. Furthermore, functional assays, such as BH3 profiling, may help in predicting responses to chemotherapies and aid in the selection of combination therapies by determining the mitochondrial threshold for initiating cell death.
Keywords: ASH, American Society of Hematology; ATAP, amphipathic tail-anchoring peptide; Apoptosis; BAD, BCL-2-associated death promoter protein; BAK, BCL-2 homologous antagonist killer; BAX, BCL-2-associated X protein; BCL-2 family; BCL-2, B-cell lymphoma 2; BCL-w (BCL2L2), BCL-2-like protein 2; BCL-xL, B-cell lymphoma X long; BCR, B-cell receptor; BFL-1 (BCL2A1), BCL-2-related protein A1; BH3 profiling; BH3, BCL-2 homology 3; BID, BH3 interacting domain death agonist; BIK, BCL-2-interacting killer; BIM, BCL-2-interacting mediator of cell death; BOK, BCL-2 related ovarian killer; BTK, Bruton׳s tyrosine kinase; CDK, cyclin-dependent kinase; CHOP, cyclophosphamide, hydroxydaunorubicin, oncovin-vincristine and prednisone; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CR, complete response;EGFR, epidermal growth factor receptor; Combination therapy; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FDA, U. S. Food and Drug Administration; GSK-3, glycogen synthase kinase-3; ITK, interleukin-2-inducible T-cell kinase; MCL, myeloid cell leukemia; MOMP, mitochondrial outer membrane permeabilization; Mitochondrial priming; NHL, non-Hodgkin lymphoma; NIH, National Institutes of Health; NSCLC, non-small cell lung cancer; PI3K, phosphatidylinositol-3-kinase; PUMA, p53 up-regulated modulator of apoptosis; SLL, small lymphocytic lymphoma; T-ALL, T-acute lymphocytic leukemia; Targeted therapy.