Ruthenium complex containing 1,3-thiazolidine-2-thione inhibits hepatic cancer stem cells by suppressing Akt/mTOR signalling and leading to apoptotic and autophagic cell death.

Autor: Neves SP; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil., Bomfim LM; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil., Kataura T; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK., Carvalho SG; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil., Nogueira ML; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil., Dias RB; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil; Department of Propedeutics, School of Dentistry of the Federal University of Bahia, Salvador, Bahia, 40110-909, Brazil; Department of Biological Sciences, State University of Feira de Santana, Feira de Santana, Bahia, 44036-900, Brazil., Valverde LF; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil; Department of Dentistry, Federal University of Sergipe, Lagarto, Sergipe, 49400-000, Brazil., Gurgel Rocha CA; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil; Department of Propedeutics, School of Dentistry of the Federal University of Bahia, Salvador, Bahia, 40110-909, Brazil; Center for Biotechnology and Cell Therapy, D'Or Institute for Research and Education (IDOR), Salvador, Bahia, 41253-190, Brazil., Soares MBP; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil; SENAI Institute of Innovation (ISI) in Health Advanced Systems, University Center SENAI/CIMATEC, Salvador, Bahia, 41650-010, Brazil., Silva MMD; Department of Chemistry, Federal University of São Carlos, São Carlos, São Paulo, 13561-901 Brazil., Batista AA; Department of Chemistry, Federal University of São Carlos, São Carlos, São Paulo, 13561-901 Brazil., Korolchuk VI; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK., Bezerra DP; Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil. Electronic address: daniel.bezerra@fiocruz.br.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Aug; Vol. 177, pp. 117059. Date of Electronic Publication: 2024 Jul 01.
DOI: 10.1016/j.biopha.2024.117059
Abstrakt: Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF 6 , to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133 + and CD44 high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5 -/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: VIK is a scientific advisor for Longaevus Technologies. All other authors declare no competing interests.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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