Drugs targeting Bcl-2 family members as an emerging strategy in cancer

Brian Leber; Fei Geng; Justin Kale; David W. Andrews

doi:10.1017/S1462399410001572

Drugs targeting Bcl-2 family members as an emerging strategy in cancer

Published online by Cambridge University Press: 08 September 2010

Brian Leber ,

Fei Geng ,

Justin Kale and

David W. Andrews

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Brian Leber: Affiliation:
Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. Departments of Biochemistry and Medicine, McMaster University, Hamilton, Ontario, Canada.
Fei Geng: Affiliation:
Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Justin Kale: Affiliation:
Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
David W. Andrews*: Affiliation:
Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
*: *Corresponding author: David W. Andrews, Departments of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Room 4H41, Hamilton, Ontario, CanadaL8N 3Z5. E-mail: [email protected]

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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.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 12 , January 2010 , e28

DOI: https://doi.org/10.1017/S1462399410001572 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2010

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Drugs targeting Bcl-2 family members as an emerging strategy in cancer

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Drugs targeting Bcl-2 family members as an emerging strategy in cancer

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