SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma

• Tipo: Artigo em Revista Científica Internacional
• Data: 2019

Autores

Gomes, S (Autor) Outra; Bosco, B (Autor) Outra; Loureiro, JB (Autor) Outra; Ramos, H (Autor) Outra; Raimundo, L (Autor) Outra; Soares, J (Autor) Outra; Nazareth, N (Autor) Outra; Barcherini, V (Autor) Outra; Domingues, L (Autor) Outra; Oliveira, C (Autor) Outra; Bisio, A (Autor) Outra; Piazza, S (Autor) Outra; Bauer, MR (Autor) Outra; Bras, JP (Autor) Outra; Almeida, MI (Autor) Outra; Gomes, C (Autor) Outra; Reis, F (Autor) Outra; Fersht, AR (Autor) Outra; Inga, A (Autor) Outra; Santos, MMM (Autor) Outra; Lucilia Saraiva (Autor) FFUP

Revista

Título: Cancers

Vol. 11

Página Final: 1151

ISSN: 2072-6694

Editora: MDPI

Indexação

ISI Web of Knowledge - 15 Citações

Scopus - 15 Citações

Outras Informações

ID Authenticus: P-00R-2V8

DOI: 10.3390/cancers11081151

Abstract (EN): Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 20