Deng, Jing2017-02-182017Deng, Jing. 2017. “How to unleash mitochondrial apoptotic blockades to kill cancers?” Acta Pharmaceutica Sinica. B 7 (1): 18-26. doi:10.1016/j.apsb.2016.08.005. http://dx.doi.org/10.1016/j.apsb.2016.08.005.2211-3835http://nrs.harvard.edu/urn-3:HUL.InstRepos:30370920Apoptosis, 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.en-USASH, American Society of HematologyATAP, amphipathic tail-anchoring peptideBAD, BCL-2-associated death promoter proteinBAK, BCL-2 homologous antagonist killerBAX, BCL-2-associated X proteinBCL-2, B-cell lymphoma 2BCL-w (BCL2L2), BCL-2-like protein 2BCL-xL, B-cell lymphoma X longBFL-1 (BCL2A1), BCL-2-related protein A1BCR, B-cell receptorBH3, BCL-2 homology 3BID, BH3 interacting domain death agonistBIK, BCL-2-interacting killerBIM, BCL-2-interacting mediator of cell deathBOK, BCL-2 related ovarian killerBTK, Bruton׳s tyrosine kinaseCDK, cyclin-dependent kinaseCLL, chronic lymphocytic leukemiaCHOP, cyclophosphamide, hydroxydaunorubicin, oncovin-vincristine and prednisoneCML, chronic myelogenous leukemiaCR, complete response;EGFR, epidermal growth factor receptorER, endoplasmic reticulumERK, extracellular signal-regulated kinaseFDA, U. S. Food and Drug AdministrationGSK-3, glycogen synthase kinase-3ITK, interleukin-2-inducible T-cell kinaseMCL, myeloid cell leukemiaMOMP, mitochondrial outer membrane permeabilizationNHL, non-Hodgkin lymphomaNIH, National Institutes of HealthNSCLC, non-small cell lung cancerPI3K, phosphatidylinositol-3-kinasePUMA, p53 up-regulated modulator of apoptosisSLL, small lymphocytic lymphomaT-ALL, T-acute lymphocytic leukemiaApoptosisBCL-2 familyMitochondrial primingBH3 profilingTargeted therapyCombination therapyJournal Article2017-02-1810.1016/j.apsb.2016.08.005