Apoptosis plays an essential role in the processes of eukaryotic cellular homeostasis, and is thought to be a contributing factor in the development of a variety of pathologies including cancer. Knowledge of the molecular mechanisms and mediators of apoptosis, coupled with the fact that many current anticancer therapies function by activating apoptosis, has led to realization that apoptotic processes not only serve as the crucial regulators of carcinogenesis but are also critical determinants in therapy responses. Defects in apoptosis signaling often lead to ineffective response to anti-cancer therapeutics in the clinic and contribute to development of drug-resistant phenotype. The mediators of apoptosis, therefore, are attractive and rational targets for design and development of apoptosis-promoting strategies to combat cancer. Here we present an overview of different approaches and proof-of-principle evidence for identification, development, and use of agents that target apoptosis signaling in cancer. A synopsis of different apoptosis pathways and the agents, currently in the clinic or in development pipeline, that target mediators of apoptosis is presented. Last, but not least, novel and emerging apoptosis signaling targets with potential utility in anti-cancer drug development are also discussed.
Keywords: Apoptosis, Caspases, p53, IAPs, Mitochondria, Nur77, CARP-1, Apoptosis Signaling Pathways, Anti-Cancer Therapeutics, eukaryotic cellular homeostasis, carcinogenesis, drug-resistant phenotype, apoptosis-promoting strategies, anti-cancer drug development, cell membrane blebbing, cell shrinkage, chromatin condensation, nucleosomal fragmentation, mitochondria-mediated pathway, extracellular receptor-activated pathway, reactive oxygen species, effector/executioner caspases, EXTRINSIC PATHWAY, tumor necrosis factor, Death Receptors, TNF-dependent signaling, TNF-related apoptosisinducing ligand, ectodysplasin A receptor, decoy receptors, FADD-like interleukin-1ß-converting enzyme inhibitory protein, intrinsic apoptosis pathway, granzymes, TRAIL stimulated apoptosis, HGS-ETR1, IFN-γ, cyclooxygenase-2 inhibitors, doxorubicin, cisplatin, etoposide, radiotherapy, FLIP expression, actinomycin D, PPARα ligands, mitochondrial outer membrane permeability, anti-apoptotic Bcl-2 proteins, tumor suppressor p53, ionizing radiation, cyclin-dependent kinase, Smac/DIA-BLO, Omi/HtrA2, protease-activating factor 1, inhibitor of apoptosis, Caenorhabditis elegans, zymogens, X-Glu-X-Asp, NF-kB activation, caspase-independent cell death, small-cell lung cancer, 5-Aza-2'-deoxycytidine, RGD peptides, second mitochondria-derived activator of caspase, IAP-binding motif, cIAP1 and cIAP2 genes, BIR3 antagonists, TWX024, Embelin, LY2181308, survivin, ANTI-APOPTOTIC BCL-2 FAMILY, Chelerythrine, Oblimersen, SAHBs, BH3Is, Cytochrome, serpin, vIAPs, viral FLICE, CARP-1 expression
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