title: Necrotic concentrations of cisplatin activate the apoptotic machinery but inhibit effector caspases and interfere with the execution of apoptosis.
abstract: Cisplatin is a chemotherapeutic drug whose cytotoxicity is key to its therapeutic and side effects. Nephrotoxicity, mainly due to renal tubular injury, poses its most important therapeutic limitation. Tubular necrosis is derived from epithelial cell death by apoptosis and necrosis in the proximal and distal tubuli. The mode of cell death has been related to drug concentration, with necrosis occurring with high concentrations and apoptosis with lower concentrations. To fully understand the toxic effects of cisplatin to potentially improve its pharmaco-toxicological profile, it is necessary to unravel the cellular events and signaling pathways implicated in the appearance of both modes of cell death. We used cultured human lymphoma and renal tubule cells to investigate the biochemical and phenotypic characteristics of the death mode induced by increasing concentrations of cisplatin. Our results indicate that pronecrotic concentrations of cisplatin early activate the apoptotic machinery, which is in turn directly blocked by cisplatin at the level of effector caspases. Aborted apoptosis induces a death phenotype lacking some typical characteristics of this process, which more closely resembles necrosis. Furthermore, unidentified Bcl-2- and mitochondria-independent pathways are induced by pronecrotic and not by proapoptotic concentrations of cisplatin. Cisplatin-induced cell necrosis is the result of an aborted apoptosis at the level of effector caspases. Yet, Bcl-2-independent effects lead to cell death, which may pose potential targets for pharmacological intervention aimed at reducing cisplatin nephrotoxicity.
authors.affiliation: Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sancho-Martínez
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Piedrafita
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Cannata-Andía
authors.forename: José M
authors.initials: JM
authors.lastname: López-Novoa
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López-Hernández
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D002945:Cisplatin