title: Arsenic trioxide (AT) is a novel human neutrophil pro-apoptotic agent: effects of catalase on AT-induced apoptosis, degradation of cytoskeletal proteins and de novo protein synthesis.
abstract: The anti-cancer drug arsenic trioxide (AT) induces apoptosis in a variety of transformed or proliferating cells. However, little is known regarding its ability to induce apoptosis in terminally differentiated cells, such as neutrophils. Because neutropenia has been reported in some cancer patients after AT treatment, we hypothesised that AT could induce neutrophil apoptosis, an issue that has never been investigated. Herein, we found that AT-induced neutrophil apoptosis and gelsolin degradation via caspases. AT did not increase neutrophil superoxide production and did not induce mitochondrial generation of reactive oxygen species. AT-induced apoptosis in PLB-985 and X-linked chronic granulomatous disease (CGD) cells (PLB-985 cells deficient in gp91(phox) mimicking CGD) at the same potency. Addition of catalase, an inhibitor of H2O2, reversed AT-induced apoptosis and degradation of the cytoskeletal proteins gelsolin, alpha-tubulin and lamin B1. Unexpectedly, AT-induced de novo protein synthesis, which was reversed by catalase. Cycloheximide partially reversed AT-induced apoptosis. We conclude that AT induces neutrophil apoptosis by a caspase-dependent mechanism and via de novo protein synthesis. H2O2 is of major importance in AT-induced neutrophil apoptosis but its production does not originate from nicotinamide adenine dinucleotide phosphate dehydrogenase activation and mitochondria. Cytoskeletal structures other than microtubules can now be considered as novel targets of AT.
authors.affiliation: INRS-Institut Armand-Frappier, Université du Québec, Pointe-Claire, PQ, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Binet
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavalli
authors.forename: Eliane
authors.initials: E
authors.lastname: Moisan
authors.forename: Denis
authors.initials: D
authors.lastname: Girard
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000378:metabolism*; D045744:Cell Line, Tumor; D018260:Gelsolin / Q000187:drug effects; D006801:Humans; D034921:Lamin Type B / Q000187:drug effects; D008840:Microfilament Proteins / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010087:Oxides / Q000494:pharmacology*; D011489:Protein Denaturation / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014404:Tubulin / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D018260:Gelsolin; D034921:Lamin Type B; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D010087:Oxides; D017382:Reactive Oxygen Species; D014404:Tubulin; D002374:Catalase; D020169:Caspases; D000077237:Arsenic Trioxide