TRAIL/Apo-2L: mechanisms and clinical applications in cancer.
TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) is a member of the TNF family that promotes apoptosis by binding to the transmembrane receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. Its cytotoxic activity is relatively selective to the human tumor cell lines without much effect on the normal cells. Hence, it exerts an antitumor activity without causing toxicity, as apparent by studies with several xenograft models. This review discusses the intracellular mechanisms by which TRAIL induces apoptosis. The major pathway of its action proceeds through the formation of DISC and activation of caspase-8. The apoptotic processes, therefore, follow two signaling pathways, namely the mitochondrial-independent activation of caspase-3, and mitochondrial-dependent apoptosis due to cleavage of BID by caspase-8, the formation of apoptosomes, and activation of caspase-9 and the downstream caspases. Bcl-2 and Bcl-X(L) have no effect on TRAIL-induced apoptosis in lymphoid cells, whereas these genes block or delay apoptosis in nonlymphoid cancer cells. TRAIL participates in cytotoxicity mediated by activated NK cells, monocytes, and some cytotoxic T cells. Hence, TRAIL may prove to be an effective antitumor agent. In addition, it may enhance the effectiveness of treatment with chemotherapeutic drugs and irradiation. Nontagged Apo-2L/TRAIL does not cause hepatotoxicity in monkeys and chimpanzees and in normal human hepatocytes. Thus, nontagged Apo-2L/TRAIL appears to be a promising new candidate for use in the treatment of cancer.
Srivastava
R K
RK
Department of Pharmaceutical Sciences, University of Maryland - School of Pharmacy Greenebaum Cancer Center, 20 North Pine Street, Baltimore, MD 21201, USA. rsrivast@rx.umaryland.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D029681:Arabidopsis Proteins; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000502:physiology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D008954:Models, Biological; D009000:Monocytes / Q000276:immunology; D016328:NF-kappa B / Q000502:physiology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy; D011323:Primates; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects* / Q000502:physiology; D012449:Safety; D015398:Signal Transduction / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D029681:Arabidopsis Proteins; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D020169:Caspases