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

• Autor(a) principal: Soares, Joana
• Data de Publicação: 2016
• Outros Autores: 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
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/108734; https://doi.org/10.18632/oncotarget.6775
• topic: Tumor; p53; mutant; tryptophanol-derived oxazoloisoindolinones; anticancer chemotherapy; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Movement; Cell Proliferation; Colonic Neoplasms; High-Throughput Screening Assays; Humans; Immunoenzyme Techniques; Isoindoles; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Oxazoles; Piperidones; RNA, Messenger; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Small Molecule Libraries; Tryptophan; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

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.