The BCL-2 arbiters of apoptosis and their growing role as cancer targets.

Abstract

Impaired apoptosis plays a central role in cancer development and limits the efficacy of conventional cytotoxic therapies. Deepening understanding of how opposing factions of the BCL-2 protein family switch on apoptosis and of their structures has driven development of a new class of cancer drugs that targets various pro-survival members by mimicking their natural inhibitors, the BH3-only proteins. These 'BH3 mimetic' drugs seem destined to become powerful new weapons in the arsenal against cancer. Successful clinical trials of venetoclax/ABT-199, a specific inhibitor of BCL-2, have led to its approval for a refractory form of chronic lymphocytic leukaemia and to scores of on-going trials for other malignancies. Furthermore, encouraging preclinical studies of BH3 mimetics that target other BCL-2 pro-survival members, particularly MCL-1, offer promise for cancers resistant to venetoclax. This review sketches the impact of the BCL-2 family on cancer development and therapy, describes how interactions of family members trigger apoptosis and discusses the potential of BH3 mimetic drugs to advance cancer therapy.

• Authors: Jerry M Adams, Suzanne Cory
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 25 Issue 1 Pg. 27-36 (01 2018) ISSN: 1476-5403 [Electronic] England
• PMID: 29099483 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BCL2 protein, human
• Bridged Bicyclo Compounds, Heterocyclic
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• venetoclax

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis
• Apoptosis Regulatory Proteins (physiology)
• Bridged Bicyclo Compounds, Heterocyclic (therapeutic use)
• Humans
• Mitochondrial Membranes (metabolism)
• Neoplasms (drug therapy)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, chemistry, metabolism, physiology)
• Sulfonamides (therapeutic use)