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

Autor: Alessandra Bisio, Bartolomeo Bosco, Helena Ramos, Flávio Reis, Carla Cristina Marques de Oliveira, Alberto Inga, Maria Inês Almeida, Célia Gomes, Silvano Piazza, Maria M. M. Santos, Lucília Domingues, Lucília Saraiva, Liliana Raimundo, Matthias R. Bauer, Alan R. Fersht, Sara Gomes, Joana Soares, Nair Nazareth, Joao Paulo Bras, Joana B. Loureiro, Valentina Barcherini
Přispěvatelé: Instituto de Investigação e Inovação em Saúde, Ramos, Helena [0000-0001-5546-9998], Raimundo, Liliana [0000-0001-9003-2601], Domingues, Lucília [0000-0003-1089-7627], Piazza, Silvano [0000-0002-7156-5434], Bauer, Matthias R [0000-0003-4015-6483], Brás, João P [0000-0003-1867-0486], Almeida, Maria Inês [0000-0003-2072-8587], Reis, Flávio [0000-0003-3401-9554], Inga, Alberto [0000-0002-8767-1637], Santos, Maria MM [0000-0002-2239-9353], Saraiva, Lucília [0000-0002-9531-4939], Apollo - University of Cambridge Repository, Universidade do Minho
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Cancers, Vol 11, Iss 8, p 1151 (2019)
Cancers
Cancers; Volume 11; Issue 8; Pages: 1151
Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
ISSN: 2072-6694
Popis: 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.
Authors acknowledge the financial support from European Union (FEDER funds POCI/01/0145/FEDER/007728 through Programa Operacional Factores de Competitividade—COMPETE) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement UID/DTP/04138/2019 (iMed.ULisboa), UID/NEU/04539/2013, UID/NEU/04539/2019. CENTRO-01-0145-FEDER-000012-HealthyAging2020, UID/BIO/04469/2019, BioTecNorte operation (NORTE-01-0145-FEDER-000004), and the projects (3599-PPCDT) PTDC/DTP-FTO/1981/2014—POCI-01-0145-FEDER-016581, and POCI-01-0145-FEDER-028736. We also thank FCT for the financial support through the grant CEECIND/01772/2017 (M. M. M. Santos), and fellowships SFRH/BD/96189/2013 (S. Gomes), PD/BD/143126/2019 (V. Barcherini), SFRH/BD/117949/2016 (L. Raimundo), SFRH/BD/119144/2016 (H. Ramos), SFRH/BD/128673/2017 (J. B. Loureiro), and the Programa Operacional Potencial Humano (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences; PD/00016/2012). We also acknowledge the support from the Italian Association for Cancer Research, AIRC (IG#18985 to AI).
Databáze: OpenAIRE
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