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Open AccessArticle

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

1
LAQV/REQUIMTE, Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
2
Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Trento, Italy
3
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
4
CEB—Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
5
Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK
6
i3S—Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
7
INEB—Institute of Biomedical Engineering, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
8
Institute 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, Portugal
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(8), 1151; https://doi.org/10.3390/cancers11081151
Received: 4 June 2019 / Revised: 25 July 2019 / Accepted: 7 August 2019 / Published: 10 August 2019
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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Abstract

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. View Full-Text
Keywords: anticancer therapeutics; hepatocellular carcinoma; Hsp70; mutant p53; tryptophanol-derived oxazoloisoindolinone anticancer therapeutics; hepatocellular carcinoma; Hsp70; mutant p53; tryptophanol-derived oxazoloisoindolinone
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Gomes, 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.

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