title: Acute cytotoxicity of MIRA-1/NSC19630, a mutant p53-reactivating small molecule, against human normal and cancer cells via a caspase-9-dependent apoptosis.
abstract: Although numerous studies have focused on the mechanisms of action of the candidate chemotherapeutic drug MIRA-1/NSC19630, initially described as a mutant p53-reactivating small molecule, the issue of its toxicological evaluation remains open. Here, we devised a strategy to examine the effects of MIRA-1 on a variety of human normal cells and cancer cell lines. First, we demonstrated a massive and rapid (within 2 hours) MIRA-1 apoptotic effect on human normal primary epithelial cells as shown using an intestinal mucosa explant assay. MIRA-1 was also cytotoxic to primary and subcultured human mesenchymal cells. Interestingly these effects were restricted to actively proliferating cells. Second, MIRA-1 acute toxicity was independent of p53, since it occurred in human normal cells with increased or silenced p53 expression level, in cancer cells derived from solid or liquid tumors, with either mutated or wt TP53, and in cancer cells devoid of p53. Third, combined pharmacological and genetic approaches showed that MIRA-1 acute cytotoxicity was mediated by a caspase-9-dependent apoptosis. In conclusion, our strategy unveils the limitations of the targeted action of a small molecule designed to reactivate mutant p53.
authors.affiliation: EA4273 Biometadys, Faculté de Médecine, Université de Nantes, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Bou-Hanna
authors.affiliation: EA4273 Biometadys, Faculté de Médecine, Université de Nantes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Jarry
authors.affiliation: Laboratoire d'Hématologie, CHU de Nantes, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lode
authors.affiliation: Systems-Oriented Immunology and Inflammation Research, Helmholtz Center for Infection Research, Braunschweig, Germany; Institute for Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
authors.affiliation: Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.affiliation: Service de Génétique Médicale, CHU de Nantes, Nantes, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Kury
authors.affiliation: EA4273 Biometadys, Faculté de Médecine, Université de Nantes, France; Service de Génétique Médicale, CHU de Nantes, Nantes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bezieau
authors.affiliation: EA4273 Biometadys, Faculté de Médecine, Université de Nantes, France; Service d'Anatomie et Cytologie Pathologiques, CHU de Nantes, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mosnier
authors.affiliation: EA4273 Biometadys, Faculté de Médecine, Université de Nantes, France; Service d'Anatomie et Cytologie Pathologiques, CHU de Nantes, France. Electronic address: christian.laboisse@chu-nantes.fr.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Laboisse
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9 / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D008875:Middle Aged; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C557741:1-(propoxymethyl)maleimide; D000970:Antineoplastic Agents; D008301:Maleimides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C506433:CASP9 protein, human; D053453:Caspase 9
keywords: Cancer cell lines; Explant culture; Growth phase; Primary normal cells; Toxicology