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Reactivation of wild-type and mutant p53 by tryptophanolderived oxazoloisoindolinone SLMP53-1, a novel anticancer small-molecule

2015; Impact Journals LLC; Volume: 7; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.6775

1949-2553

Joana Soares, Liliana Raimundo, Nuno A. L. Pereira, Ângelo Monteiro, Sara Gomes, Cláudia Bessa, Clara Pereira, Glória Queiróz, Alessandra Bisio, João Carlos Fernandes, Célia Gomes, Flávio Reis, Jorge Gonçalves, Alberto Inga, Maria M. M. Santos, Lucı́lia Saraiva,

Ubiquitin and proteasome pathways

// Joana Soares 1, 2 , Liliana Raimundo 1, 2 , Nuno A.L. Pereira 4 , Ângelo Monteiro 4 , Sara Gomes 1, 2 , Cláudia Bessa 1, 2 , Clara Pereira 1, 2 , Glória Queiroz 3 , Alessandra Bisio 5 , João Fernandes 6 , Célia Gomes 6 , Flávio Reis 6 , Jorge Gonçalves 3 , Alberto Inga 5 , Maria M.M. Santos 4 , Lucília Saraiva 1, 2 1 UCIBIO/REQUIMTE, Universidade do Porto, Porto, Portugal 2 Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal 3 Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal 4 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal 5 CIBIO, Centre for Integrative Biology, Laboratory of Transcriptional Networks, University of Trento, Trento, Italy 6 Laboratório de Farmacologia e Terapêutica Experimental, IBILI, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal Correspondence to: Maria M.M. Santos, e-mail: mariasantos@ff.ulisboa.pt Lucília Saraiva, e-mail: lucilia.saraiva@ff.up.pt Keywords: tumor, p53, mutant, tryptophanol-derived oxazoloisoindolinones, anticancer chemotherapy Received: June 17, 2015 Accepted: November 28, 2015 Published: December 28, 2015 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.