TY - JOUR
T1 - SLMP53-2 restoreswild-type-like function to mutant p53 through hsp70
T2 - promising activity in hepatocellular carcinoma
AU - Gomes, Sara
AU - Bosco, Bartolomeo
AU - Loureiro, Joana B.
AU - Ramos, Helena
AU - Raimundo, Liliana
AU - Soares, Joana
AU - Nazareth, Nair
AU - Barcherini, Valentina
AU - Domingues, Lucília
AU - Oliveira, Carla
AU - Bisio, Alessandra
AU - Piazza, Silvano
AU - Bauer, Matthias R.
AU - Brás, João P.
AU - Almeida, Maria Inês
AU - Gomes, Célia
AU - Reis, Flávio
AU - Fersht, Alan R.
AU - Inga, Alberto
AU - Santos, Maria M. M.
AU - Saraiva, Lucília
N1 - Funding Information:
Acknowledgments: 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).
Funding Information:
This work was supported by National Funds through Funda??o para a Ci?ncia e Tecnologia, I.P. via the projects UID/QUI/50006/2019 and PTDC/QUI-QOR/29664/2017.
Funding Information:
Funding: This work was supported by National Funds through Fundação para a Ciência e Tecnologia, I.P. via the projects UID/QUI/50006/2019 and PTDC/QUI-QOR/29664/2017.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/8
Y1 - 2019/8
N2 - 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 structuralmutp53. 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.
AB - 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 structuralmutp53. 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.
KW - Anticancer therapeutics
KW - Hepatocellular carcinoma
KW - Hsp70
KW - Mutant p53
KW - Tryptophanol-derived oxazoloisoindolinone
UR - http://www.scopus.com/inward/record.url?scp=85073295665&partnerID=8YFLogxK
U2 - 10.3390/cancers11081151
DO - 10.3390/cancers11081151
M3 - Article
AN - SCOPUS:85073295665
SN - 2072-6694
VL - 11
JO - Cancers
JF - Cancers
IS - 8
M1 - 1151
ER -