title: Drugs targeting Bcl-2 family members as an emerging strategy in cancer.
abstract: Inhibiting apoptosis is widely accepted as a necessary step in the transition from normal to cancer cells, and most cancer therapies exert their effects by indirectly reversing this process. Commitment to apoptosis is caused by permeabilisation of the outer mitochondrial membrane--a process regulated by the binding between different members of the Bcl-2 family. Furthermore, Bcl-2 family members also bind to the endoplasmic reticulum, where they modify processes such as the unfolded-protein response and autophagy that also cause or modify different types of cell death. With the growing understanding of the importance of the Bcl-2 family as crucial regulators of the decision to initiate apoptosis, much effort has been directed at developing small molecules that modify function by directly binding to Bcl-2 proteins. Preclinical experiments have confirmed that these agents kill cancer cells and overcome chemotherapy resistance. Two of these drugs are in the initial stages of clinical development (ABT-263 and obatoclax), and early results show clinical efficacy at tolerable doses. Important questions for the future include the role of these drugs as monotherapy versus combination therapy with other anticancer drugs, and the related issue of the relative toxicity to cancerous versus normal cells.
authors.affiliation: Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.forename: Fei
authors.initials: F
authors.lastname: Geng
authors.forename: Justin
authors.initials: J
authors.lastname: Kale
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D006801:Humans; D007211:Indoles; D009369:Neoplasms / Q000188:drug therapy*; D011485:Protein Binding / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D013449:Sulfonamides; C520962:obatoclax; C528561:navitoclax