SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma
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 re...
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MDPI AG
2019-08-01
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Series: | Cancers |
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Online Access: | https://www.mdpi.com/2072-6694/11/8/1151 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sara Gomes Bartolomeo Bosco Joana B. Loureiro Helena Ramos Liliana Raimundo Joana Soares Nair Nazareth Valentina Barcherini Lucília Domingues Carla Oliveira Alessandra Bisio Silvano Piazza Matthias R. Bauer João P. Brás Maria Inês Almeida Célia Gomes Flávio Reis Alan R. Fersht Alberto Inga Maria M. M. Santos Lucília Saraiva |
spellingShingle |
Sara Gomes Bartolomeo Bosco Joana B. Loureiro Helena Ramos Liliana Raimundo Joana Soares Nair Nazareth Valentina Barcherini Lucília Domingues Carla Oliveira Alessandra Bisio Silvano Piazza Matthias R. Bauer João P. Brás Maria Inês Almeida Célia Gomes Flávio Reis Alan R. Fersht Alberto Inga Maria M. M. Santos Lucília Saraiva SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma Cancers anticancer therapeutics hepatocellular carcinoma Hsp70 mutant p53 tryptophanol-derived oxazoloisoindolinone |
author_facet |
Sara Gomes Bartolomeo Bosco Joana B. Loureiro Helena Ramos Liliana Raimundo Joana Soares Nair Nazareth Valentina Barcherini Lucília Domingues Carla Oliveira Alessandra Bisio Silvano Piazza Matthias R. Bauer João P. Brás Maria Inês Almeida Célia Gomes Flávio Reis Alan R. Fersht Alberto Inga Maria M. M. Santos Lucília Saraiva |
author_sort |
Sara Gomes |
title |
SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma |
title_short |
SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma |
title_full |
SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma |
title_fullStr |
SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma |
title_full_unstemmed |
SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma |
title_sort |
slmp53-2 restores wild-type-like function to mutant p53 through hsp70: promising activity in hepatocellular carcinoma |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2019-08-01 |
description |
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. |
topic |
anticancer therapeutics hepatocellular carcinoma Hsp70 mutant p53 tryptophanol-derived oxazoloisoindolinone |
url |
https://www.mdpi.com/2072-6694/11/8/1151 |
work_keys_str_mv |
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doaj-c177f36347c647be9bc88a72036760562020-11-25T01:58:49ZengMDPI AGCancers2072-66942019-08-01118115110.3390/cancers11081151cancers11081151SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular CarcinomaSara Gomes0Bartolomeo Bosco1Joana B. Loureiro2Helena Ramos3Liliana Raimundo4Joana Soares5Nair Nazareth6Valentina Barcherini7Lucília Domingues8Carla Oliveira9Alessandra Bisio10Silvano Piazza11Matthias R. Bauer12João P. Brás13Maria Inês Almeida14Célia Gomes15Flávio Reis16Alan R. Fersht17Alberto Inga18Maria M. M. Santos19Lucília Saraiva20LAQV/REQUIMTE, Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalDepartment of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, ItalyLAQV/REQUIMTE, Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalLAQV/REQUIMTE, Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalLAQV/REQUIMTE, Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalLAQV/REQUIMTE, Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalLAQV/REQUIMTE, Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalCEB—Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, PortugalCEB—Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, PortugalDepartment of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, ItalyDepartment of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, ItalyMedical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UKi3S—Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugali3S—Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, PortugalInstitute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, CNC.IBILI Consortium & CIBB Consortium, University of Coimbra, 3000-548 Coimbra, PortugalInstitute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, CNC.IBILI Consortium & CIBB Consortium, University of Coimbra, 3000-548 Coimbra, PortugalMedical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UKDepartment of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, ItalyResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalLAQV/REQUIMTE, Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, PortugalHalf 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.https://www.mdpi.com/2072-6694/11/8/1151anticancer therapeuticshepatocellular carcinomaHsp70mutant p53tryptophanol-derived oxazoloisoindolinone |