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lüll Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy Kang MH; Reynolds CPClin Cancer Res 2009[Feb]; 15 (4): 1126-32Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic pathway. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins. Overexpression of anti-apoptotic Bcl-2 family members has been associated with chemotherapy resistance in various human cancers, and preclinical studies have shown that agents targeting anti-apoptotic Bcl-2 family members have preclinical activity as single agents and in combination with other antineoplastic agents. Clinical trials of several investigational drugs targeting the Bcl-2 family (oblimersen sodium, AT-101, ABT-263, GX15-070) are ongoing. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.|Aniline Compounds/pharmacology[MESH]|Animals[MESH]|Antineoplastic Agents/*pharmacology[MESH]|Apoptosis/*drug effects[MESH]|Biphenyl Compounds/pharmacology[MESH]|Gossypol/pharmacology[MESH]|Humans[MESH]|Indoles[MESH]|Mitochondria/*drug effects[MESH]|Neoplasms/drug therapy/pathology[MESH]|Nitrophenols/pharmacology[MESH]|Piperazines/pharmacology[MESH]|Proto-Oncogene Proteins c-bcl-2/*antagonists & inhibitors[MESH]|Pyrroles/pharmacology[MESH]|Sulfonamides/pharmacology[MESH]|Thionucleotides/therapeutic use[MESH] |