Autor(es):
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
Data: 2016
Identificador Persistente: https://hdl.handle.net/10316/108734
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): 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
Descrição
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.
