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Title: | Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule | Authors: | Soares, Joana Raimundo, Liliana Pereira, Nuno A. L. Monteiro, Ângelo Gomes, Sara Bessa, Cláudia Pereira, Clara Queiroz, Glória Bisio, Alessandra Fernandes, João Gomes, Célia Reis, Flávio Gonçalves, Jorge Inga, Alberto Santos, Maria M. M. Saraiva, Lucília |
Keywords: | Tumor; p53; mutant; tryptophanol-derived oxazoloisoindolinones; anticancer chemotherapy | Issue Date: | 26-Jan-2016 | Publisher: | Impact Journals | Project: | UID/Multi/04378/2013 (UCIBIO/REQUIMTE) SFRH/BD/78971/2011 PD/ BI/113926/2015) SFRH/BD/96189/2013 SFRH/BD/87109/2012 IF Program (IF/00732/2013) |
Serial title, monograph or event: | Oncotarget | Volume: | 7 | Issue: | 4 | Abstract: | Restoration of the p53 pathway, namely by reactivation of mutant (mut) p53, represents a valuable anticancer strategy. Herein, we report the identification of the enantiopure tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a novel reactivator of wild-type (wt) and mut p53, using a yeast-based screening strategy. SLMP53-1 has a p53-dependent anti-proliferative activity in human wt and mut p53R280K-expressing tumor cells. Additionally, SLMP53-1 enhances p53 transcriptional activity and restores wt-like DNA binding ability to mut p53R280K. In wt/mut p53-expressing tumor cells, SLMP53-1 triggers p53 transcription-dependent and mitochondrial apoptotic pathways involving BAX, and wt/mut p53 mitochondrial translocation. SLMP53-1 inhibits the migration of wt/mut p53-expressing tumor cells, and it shows promising p53-dependent synergistic effects with conventional chemotherapeutics. In xenograft mice models, SLMP53-1 inhibits the growth of wt/mut p53-expressing tumors, but not of p53-null tumors, without apparent toxicity. Collectively, besides the potential use of SLMP53-1 as anticancer drug, the tryptophanol-derived oxazoloisoindolinone scaffold represents a promissing starting point for the development of effective p53-reactivating drugs. | URI: | https://hdl.handle.net/10316/108734 | ISSN: | 1949-2553 | DOI: | 10.18632/oncotarget.6775 | Rights: | openAccess |
Appears in Collections: | I&D IBILI - Artigos em Revistas Internacionais FMUC Medicina - Artigos em Revistas Internacionais |
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Reactivation-of-wildtype-and-mutant-p53-by-tryptophanolderived-oxazoloisoindolinone-SLMP531-a-novel-anticancer-smallmoleculeOncotarget.pdf | 4.75 MB | Adobe PDF | View/Open |
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