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Fundam Clin Pharmacol. 2019 Jan 9. doi: 10.1111/fcp.12447. [Epub ahead of print]

In silico analysis of the binding properties of solasonine to mortalin and p53, and in vitro pharmacological studies of its apoptotic and cytotoxic effects on human HepG2 and Hep3b hepatocellular carcinoma cells.

Author information

1
Université de Toulouse, UPS, UMR 152 Pharma-DEV, Université Toulouse 3, Faculté des Sciences Pharmaceutiques, 35 Chemin des Maraîchers, F-31062, Toulouse cedex 9, France.
2
Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, Building 1H, 18 Hoang Quoc Viet, Hanoi, Vietnam.
3
Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Hanoi, Vietnam.
4
Vietnam University of Traditional Medicine, Ministry of Health, 2 Tran Phu, Hanoi, Vietnam.

Abstract

Liver cancer, of which human hepatocellular carcinoma (HCC) is the most common type, represents the second most common cause of death from cancer worldwide. To date, treatments remain mostly ineffective and efforts are made to discover new molecules or therapeutic strategies against HCC. Mortalin, an hsp70 chaperone protein, is overexpressed in various cancer, including HCC. Mortalin sequesters p53 into the cytoplasm, thereby inhibiting its translocation to the nucleus and consequently, its cellular functions. Inhibition of mortalin - p53 interactions, which should activate the apoptotic process and the subsequent cell death, has thus been proposed as an anticancer strategy. In silico screening of a database of 354 natural compounds identified solasonine, a steroidal glycoalkaloid from Solanaceae, as a potent inhibitor of p53 - mortalin interactions. Pharmacological studies confirmed that solasonine was able to inhibit efficiently mortalin - p53 interaction in HCC HepG2 cell line that expresses both mortalin and p53. This resulted in p53 translocation to the nucleus. Solasonine induced apoptosis and cell death of HCC cell lines either expressing p53 (HepG2) or not (Hep3b), indicating that apoptotic activities of solasonine can be mediated not only through p53-dependent but also p53-independent pathways. The cytotoxic effects of solasonine correlated in part with its apoptotic properties and differed in the two HCC cell lines, being reversed by pifithrin-α, an inhibitor of p53 functions, in HepG2 cells but not in Hep3b cells. Non apoptotic cell death was also observed, notably in Hep3b cells. This article is protected by copyright. All rights reserved.

KEYWORDS:

apoptosis; cell death; hepatocellular carcinoma; in silico screening; mortalin - p53 inhibitor; solasonine

PMID:
30628118
DOI:
10.1111/fcp.12447

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