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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(s) -
Pham Minh Quan,
Tran Thi Hoai Van,
Pham Quoc Long,
Gairin Jean Edouard
Publication year - 2019
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12447
Subject(s) - apoptosis , cell culture , in silico , cancer research , programmed cell death , cytotoxic t cell , cancer cell , hepatocellular carcinoma , biology , cell , liver cancer , chemistry , in vitro , cancer , biochemistry , gene , genetics
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. Nonapoptotic cell death was also observed, notably in Hep3b cells.