Apoptosis, the major form of controlled cell death, has a key role in the pathogenesis of diseases including cancer, inflammation and neurodegenerative disorders. The past decade has witnessed tremendous progress in understanding of the molecular mechanisms of apoptosis regulation, which has revealed a number of highly promising therapeutic targets, particularly for anticancer strategies.
This special focus provides a cutting-edge overview of the science and business of targeting apoptosis, highlighting innovative therapeutic strategies and agents in clinical trials, and discussing the challenges in realizing their potential. Articles in the focus will be freely available until June 15 2009.
Supported by Genentech, Inc.
Editorial
Apoptosis: a clinical perspective
Ernest C. Borden, Harriet Kluger & John Crowley
doi:10.1038/nrd2756
Nature Reviews Drug Discovery 7, 959 (2008)
Reviews
BCL-2 family antagonists for cancer therapy
Guillaume Lessene, Peter E. Czabotar & Peter M. Colman
doi:10.1038/nrd2658
Nature Reviews Drug Discovery 7, 989-1000 (2008)
The pro-survival BCL-2 family of proteins provides exciting drug targets for the selective induction of apoptosis in cancer cells, in which these proteins are often overexpressed. Lessene and colleagues review the preclinical and clinical data for BCL-2 antagonists, and recommend criteria for establishing the mode of action for this new drug class.
Directing cancer cells to self-destruct with pro-apoptotic receptor agonists
Avi Ashkenazi
doi:10.1038/nrd2637
Nature Reviews Drug Discovery 7, 1001-1012 (2008)
Pro-apoptotic receptor agonists have a remarkable ability to selectively induce apoptosis in a wide spectrum of malignant cells. Ashkenazi discusses the scientific rationale, emerging clinical data and future potential for this exciting new class of anti-cancer drugs.
Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities
Inki Kim, Wenjie Xu & John C. Reed
doi:10.1038/nrd2755
Nature Reviews Drug Discovery 7, 1013-1030 (2008)
Endoplasmic reticulum (ER) stress is induced following the accumulation of unfolded proteins in the ER. This triggers the unfolded protein response, which initially acts to compensate for damage, but if prolonged or excessive can trigger cell death. Here, Reed and colleagues discuss the role of ER-initiated cell death pathways in diseases including neurodegeneration, hypoxia, heart disease, diabetes and immune disorders, while identifying promising therapeutic targets.
Double-edged swords as cancer therapeutics: simultaneously targeting p53 and NF-B pathways
Anwesha Dey, Vinay Tergaonkar & David P. Lane
doi:10.1038/nrd2759
Nature Reviews Drug Discovery 7, 1031-1040 (2008)
Apoptosis can be induced by activating/stabilizing p53, and by inhibiting NF-B. Now, it has been found that a surprising number of small molecules can do both. This article describes the principles behind such dual activity, discusses current candidate molecules and provides an outlook to their future development as anticancer drugs.
Perspectives
The genetics of the p53 pathway, apoptosis and cancer therapy
Alexei Vazquez, Elisabeth E. Bond, Arnold J. Levine & Gareth L. Bond
doi:10.1038/nrd2656
Nature Reviews Drug Discovery 7, 979-987 (2008)
The p53 tumour suppressor pathway is an attractive target for the development of anticancer therapies. This Perspective highlights recent progress with agents that modulate components of the p53 pathway — in particular, p53 itself and its negative regulator MDM2 — focusing on how studies of their genetic variations, including mutations in cancer cells and inherited polymorphisms, could help tailor the use of existing agents and aid the development of novel drugs.
News and Analysis
Targeting apoptosis: selected anticancer strategies
Shane Storey
doi:10.1038/nrd2662
Nature Reviews Drug Discovery 7, 971-972 (2008)
Research highlight
Apoptosis: New strategies to tip the BCL-2 balance
Alexandra Flemming
doi:10.1038/nrd2773
Nature Reviews Drug Discovery 7, 977 (2008)
Careers and recruitment
Drug discovery targeting apoptosis
doi:10.1038/nrd2765
Nature Reviews Drug Discovery 7, 1041 (2008)