title: Acid sphingomyelinase deficiency protects from cisplatin-induced gastrointestinal damage.
abstract: Cisplatin is one of the most effectively used chemotherapeutic agents for cancer treatment. However, in humans, important cytotoxic side effects are observed including dose-limiting renal damage and profound gastrointestinal symptomatology. The toxic responses to cisplatin in mice are similar to those in human patients. Here, we evaluated whether the acid sphingomyelinase (Asm) mediates at least some of the toxic in vivo effects of cisplatin. To this end, we determined the toxic effects of a single intraperitoneal dose of cisplatin (27 mg/kg) in wild type (Asm(+/+)) and Asm-deficient mice (Asm(-/-)). Tissue injury and apoptosis were determined histologically on hematoxylin-eosin and TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated nick end labeling) stainings 3, 12, 36 and 72 h after treatment. Our results revealed severe toxicity of cisplatin in Asm(+/+) mice with increased numbers of apoptotic cells in the thymus and small intestine. In marked contrast, Asm(-/-) mice were resistant to cisplatin and no apoptosis was observed in these organs after treatment. Moreover, cisplatin treatment primarily triggered apoptosis of endothelial cells in microvessels of intestine and thymus, an effect that was absent in mice lacking Asm. The data thus suggest that at least some toxic effects of cisplatin are mediated by the Asm in vivo resulting in early death of endothelial cells and consecutive organ damage.
authors.affiliation: Inserm, UMR620, IFR 140 GFAS, Rennes, France.
authors.forename: A
authors.initials: A
authors.lastname: Rebillard
authors.forename: N
authors.initials: N
authors.lastname: Rioux-Leclercq
authors.forename: C
authors.initials: C
authors.lastname: Muller
authors.forename: P
authors.initials: P
authors.lastname: Bellaud
authors.forename: F
authors.initials: F
authors.lastname: Jouan
authors.forename: O
authors.initials: O
authors.lastname: Meurette
authors.forename: E
authors.initials: E
authors.lastname: Jouan
authors.forename: L
authors.initials: L
authors.lastname: Vernhet
authors.forename: C
authors.initials: C
authors.lastname: Le Quément
authors.forename: A
authors.initials: A
authors.lastname: Carpinteiro
authors.forename: M
authors.initials: M
authors.lastname: Schenck
authors.forename: D
authors.initials: D
authors.lastname: Lagadic-Gossmann
authors.forename: E
authors.initials: E
authors.lastname: Gulbins
authors.forename: M T
authors.initials: MT
authors.lastname: Dimanche-Boitrel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics*; D004353:Drug Evaluation, Preclinical; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000473:pathology; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016158:Genes, p53; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D002945:Cisplatin