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-kappaB 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-kappaB. 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.

Top

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)

Top

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)

Top