期刊
CANCER LETTERS
卷 359, 期 2, 页码 211-217出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2015.01.014
关键词
Growth phase; Toxicology; Explant culture; Primary normal cells; Cancer cell lines
类别
资金
- University of Nantes
- Projet Hospitalier de Recherche Clinique of the French 'Direction de l'Hospitalisation et des Soins' (DHOS) [BRD 07/7-B]
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 hurnan 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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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