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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

Lookup NU author(s): Dr Tetsushi Kataura, Professor Viktor KorolchukORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2024 The AuthorsHepatic 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)]PF6, 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 CD44high 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.


Publication metadata

Author(s): Neves SP, Bomfim LM, Kataura T, Carvalho SG, Nogueira ML, Dias RB, Valverde LDF, Gurgel Rocha CA, Soares MBP, Silva MMD, Batista AA, Korolchuk VI, Bezerra DP

Publication type: Article

Publication status: Published

Journal: Biomedicine and Pharmacotherapy

Year: 2024

Volume: 177

Print publication date: 01/08/2024

Online publication date: 01/07/2024

Acceptance date: 02/04/2024

Date deposited: 15/07/2024

ISSN (print): 0753-3322

ISSN (electronic): 1950-6007

Publisher: Elsevier Masson s.r.l.

URL: https://doi.org/10.1016/j.biopha.2024.117059

DOI: 10.1016/j.biopha.2024.117059

Data Access Statement: Data will be made available on request.

PubMed id: 38955086


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Funding

Funder referenceFunder name
001Depaul UK
001Human Eye
001Focusound
001GTP Innovations Ltd
307619/2021-4
CAPES, code 001
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Fundação à Pesquisa do Estado da Bahia
Fundação à Pesquisa do Estado de São Paulo
Fundação Oswaldo Cruz
INOVA-FIOCRUZ
International Medical Research Foundation (Japan)
Uehara Memorial Foundation
VPPCB-007-FIO-18

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