title: Molecular Pathways: Leveraging the BCL-2 Interactome to Kill Cancer Cells--Mitochondrial Outer Membrane Permeabilization and Beyond.
abstract: The inhibition of apoptosis enables the survival and proliferation of tumors and contributes to resistance to conventional chemotherapy agents and is therefore a very promising avenue for the development of new agents that will enhance current cancer therapies. The BCL-2 family proteins orchestrate apoptosis at the mitochondria and endoplasmic reticulum and are involved in other processes such as autophagy and unfolded protein response (UPR) that lead to different types of cell death. Over the past decade, significant efforts have been made to restore apoptosis using small molecules that modulate the activity of BCL-2 family proteins. The small molecule ABT-199, which antagonizes the activity of BCL-2, is currently the furthest in clinical trials and shows promising activity in many lymphoid malignancies as a single agent and in combination with conventional chemotherapy agents. Here, we discuss strategies to improve the specificity of pharmacologically modulating various antiapoptotic BCL-2 family proteins, review additional BCL-2 family protein interactions that can be exploited for the improvement of conventional anticancer therapies, and highlight important points of consideration for assessing the activity of small-molecule BCL-2 family protein modulators.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hetal
authors.initials: H
authors.lastname: Brahmbhatt
authors.affiliation: Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sina
authors.initials: S
authors.lastname: Oppermann
authors.affiliation: Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada. Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Osterlund
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada. Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. david.andrews@sri.utoronto.ca.
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002463:Cell Membrane Permeability; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction; D057170:Translational Research, Biomedical
chemical_list: D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2