title: TRAIL, FasL and a blocking anti-DR5 antibody augment paclitaxel-induced apoptosis in human non-small-cell lung cancer.
abstract: Lung carcinoma is one of the most frequent causes of malignancy-related mortality in the world. Paclitaxel (PA) is an antineoplastic agent used in the treatment of non-small-cell lung cancer (NSCLC) and possesses a single-agent response rate approaching 25%. PA kills tumor cells by inducing both cellular necrosis and apoptosis. Fas and Trail receptors (DR4 and DR5) are TNF family members and act as death signal transduction proteins in the apoptosis cascade. Despite the importance of PA in lung cancer treatment, the function of Fas, DR4 and DR5 in PA-induced apoptosis, as well as the effect of their respective ligands FasL and TRAIL alone or in combination with PA, remains poorly understood. We show here that 10 microM PA induces a significant 10- to 57-fold increase in primary lung cancer cell apoptosis and is associated with 20-215% increases in caspase-3 activity in various NSCLC cell types. All the lung cancer cells express Fas, FasL, DR4 and DR5; however PA did not significantly modify their levels. We provide here the first time evidence that TRAIL is a potent inducer of apoptosis in multiple NSCLC cell lines. Noticeably, CH11, the Fas receptor cross-linking and the antagonistic anti-DR5 antibody enhance considerably the spontaneous apoptotic rate in 3 out of 5 cell types. The combination treatments, FasL+PA, TRAIL+PA or PA+anti-DR5 antibody, greatly enhance PA-apoptotic effect in most cell lines. These data suggest that the use of new combination treatment with PA and ligands targeting Fas or TRAIL receptors would be particularly efficacious.
authors.affiliation: Biological Therapeutics Laboratory, Biomedical Science Tower, University of Pittsburgh, Pittsburgh, PA 15213, USA. odouxc@msx.upmc.edu
authors.forename: Christine
authors.initials: C
authors.lastname: Odoux
authors.forename: Andreas
authors.initials: A
authors.lastname: Albers
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Amoscato
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Michael K K
authors.initials: MK
authors.lastname: Wong
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; 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; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D017239:Paclitaxel