Role of Apoptosis in Colon Cancer Biology, Therapy, and Prevention
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MOLECULAR BIOLOGY (S ANANT, SECTION EDITOR)
Role of Apoptosis in Colon Cancer Biology, Therapy, and Prevention Lin Zhang & Jian Yu
Published online: 1 October 2013 # Springer Science+Business Media New York 2013
Abstract Deregulation of apoptosis is a hallmark of human cancer and contributes to therapeutic resistance. Recent advances in cancer genomics have revealed a myriad of alterations in key pathways that directly or indirectly increase tumor cell survival. This review outlines the pathways of apoptosis in mammalian cells, and highlights the common alterations of apoptosis regulators found in colon cancer, the role of apoptosis, and underlying mechanisms in colon cancer treatment and prevention, including recent advances in investigational agents, such as kinase inhibitors, proteasome inhibitors, heat shock protein 90 inhibitors, BH3 mimetics, tumor necrosis factor related apoptosis-inducing ligand, and inhibitor of apoptosis protein antagonists. The topics also include novel concepts as well as opportunities and challenges for drug discovery and combination therapy by exploring cancerspecific genetic defects, and therefore selective induction of apoptosis in cancer cells. Although the emphasis is on colon cancer, the main theme and many of the aspects are applicable to other solid tumors. Keywords Apoptosis . Colon cancer . Bcl-2 family . BH3-only protein . Mitochondria . Death receptor . Tumor L. Zhang : J. Yu University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA L. Zhang Department of Pharmacology & Chemical Biology, Pittsburgh, PA 15213, USA J. Yu Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA J. Yu (*) Hillman Cancer Center Research Pavilion, Office Suite 2.26H, 5117 Centre Ave, Pittsburgh, PA 15213, USA e-mail: [email protected]
necrosis factor related apoptosis-inducing ligand . Epidermal growth factor receptor . KRAS . B-Raf . c-Myc . Phosphatidylinositol 3-kinase . Inhibitor of apoptosis proteins . Targeted therapies . Sorafenib . Regorafenib . Vemurafenib . Protesome inhibitors . Heat shock protein 90 inhibitors . Autophagy . Necrosis . BH3 mimetics . SMAC mimetics . Nonsteroidal anti-inflammatory drugs . Synthetic lethality
Introduction Apoptosis, also known as programmed cell death, is an evolutionarily conserved cell suicidal process essential for managing stress and maintaining tissue homeostasis in multicellular organisms. It consists of a series of well-ordered biochemical events which are regulated by a network of proteins containing distinctive functional domains. Apoptosis serves as a safeguard mechanism against tumorigenesis. During oncogenic transformation, neoplastic cells become resistant to apoptosis as a result of genetic and epigenetic alterations [1]. Defective apoptosis regulation drives other tumorigenic events, such as extended lifespan, accumulation of further genetic mutations, growth under stress conditions, and tumor angiogenesis and metastasis, and contributes to therapeutic resistance [1]. Colorectal cancer is on
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