Utilize este identificador para referenciar este registo: https://hdl.handle.net/1822/61321

TítuloSLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma
Autor(es)Gomes, Sara
Bosco, Bartolomeo
Loureiro, Joana B.
Ramos, Helena
Raimundo, Liliana
Soares, Joana
Nazareth, Nair
Barcherini, Valentina
Domingues, Lucília
Oliveira, Carla
Bisio, Alessandra
Piazza, Silvano
Bauer, Matthias R.
Brás, João P.
Almeida, Maria Inês
Gomes, Célia
Reis, Flávio
Fersht, Alan R.
Inga, Alberto
Santos, Maria M. M.
Saraiva, Lucília
Palavras-chaveanticancer therapeutics
hepatocellular carcinoma
Hsp70
mutant p53
tryptophanol-derived oxazoloisoindolinone
Data10-Ago-2019
EditoraMultidisciplinary Digital Publishing Institute
RevistaCancers
CitaçãoGomes, S.; Bosco, B.; Loureiro, J.B.; Ramos, H.; Raimundo, L.; Soares, J.; Nazareth, N.; Barcherini, V.; Domingues, L.; Oliveira, C.; Bisio, A.; Piazza, S.; Bauer, M.R.; Brás, J.P.; Almeida, M.I.; Gomes, C.; Reis, F.; Fersht, A.R.; Inga, A.; Santos, M.M.M.; Saraiva, L. SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma. Cancers 2019, 11, 1151.
Resumo(s)Half of human cancers harbor <i>TP53</i> 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.
TipoArtigo
URIhttps://hdl.handle.net/1822/61321
DOI10.3390/cancers11081151
Versão da editorahttps://www.mdpi.com/2072-6694/11/8/1151
Arbitragem científicayes
AcessoAcesso aberto
Aparece nas coleções:CEB - Publicações em Revistas/Séries Internacionais / Publications in International Journals/Series

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