Puneet Singh1, Bora Lim2,3. 1. Division of Surgery, Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Psingh6@mdanderson.org. 2. Breast Oncology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA. Bora.Lim@bcm.edu. 3. Dan L. Duncan Comprehensive Cancer Center, Houston, TX, 7200 Cambridge St.77030, USA. Bora.Lim@bcm.edu.
Abstract
PURPOSE OF REVIEW: Apoptosis is a major mechanism of cancer cell death. Thus, evasion of apoptosis results in therapy resistance. Here, we review apoptosis modulators in cancer and their recent developments, including MDM2 inhibitors and kinase inhibitors that can induce effective apoptosis. RECENT FINDINGS: Both extrinsic pathways (external stimuli through cell surface death receptor) and intrinsic pathways (mitochondrial-mediated regulation upon genotoxic stress) regulate the complex process of apoptosis through orchestration of various proteins such as members of the BCL-2 family. Dysregulation within these complex steps can result in evasion of apoptosis. However, via the combined evolution of medicinal chemistry and molecular biology, omics assays have led to innovative inducers of apoptosis and inhibitors of anti-apoptotic regulators. Many of these agents are now being tested in cancer patients in early-phase trials. We believe that despite a sluggish speed of development, apoptosis targeting holds promise as a relevant strategy in cancer therapeutics.
PURPOSE OF REVIEW: Apoptosis is a major mechanism of cancer cell death. Thus, evasion of apoptosis results in therapy resistance. Here, we review apoptosis modulators in cancer and their recent developments, including MDM2 inhibitors and kinase inhibitors that can induce effective apoptosis. RECENT FINDINGS: Both extrinsic pathways (external stimuli through cell surface death receptor) and intrinsic pathways (mitochondrial-mediated regulation upon genotoxic stress) regulate the complex process of apoptosis through orchestration of various proteins such as members of the BCL-2 family. Dysregulation within these complex steps can result in evasion of apoptosis. However, via the combined evolution of medicinal chemistry and molecular biology, omics assays have led to innovative inducers of apoptosis and inhibitors of anti-apoptotic regulators. Many of these agents are now being tested in cancer patients in early-phase trials. We believe that despite a sluggish speed of development, apoptosis targeting holds promise as a relevant strategy in cancer therapeutics.
Authors: Dominic Stadel; Andrea Mohr; Caroline Ref; Marion MacFarlane; Shaoxia Zhou; Robin Humphreys; Max Bachem; Gerry Cohen; Peter Möller; Ralf M Zwacka; Klaus-Michael Debatin; Simone Fulda Journal: Clin Cancer Res Date: 2010-10-12 Impact factor: 12.531