Author | Silva, Valdenizia R. | |
Author | Santos, Luciano de S. | |
Author | Castro, Maria V. L. de | |
Author | Dias, Rosane B. | |
Author | Valverde, Ludmila de F. | |
Author | Rocha, Clarissa A. G. | |
Author | Soares, Milena B. P. | |
Author | Quadros, Claudio A. | |
Author | Correa, Rodrigo S. | |
Author | Batista, Alzir A. | |
Author | Bezerra, Daniel P. | |
Access date | 2024-04-24T16:58:42Z | |
Available date | 2024-04-24T16:58:42Z | |
Document date | 2023 | |
Citation | SILVA, Valdenizia R. et al. A novel ruthenium complex with 5-fluorouracil suppresses colorectal cancer stem cells by inhibiting Akt/mTOR signaling. Cell Death Discovery, v. 9, p. 1-13, 2023. | en_US |
ISSN | 2058-7716 | en_US |
URI | https://www.arca.fiocruz.br/handle/icict/63660 | |
Sponsorship | Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
Fundação Oswaldo Cruz; Programa de Excelência em Pesquisa (PROEP).
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). | en_US |
Language | eng | en_US |
Publisher | Springer Nature | en_US |
Rights | open access | en_US |
Subject in Portuguese | Complexo de rutênio | en_US |
Subject in Portuguese | 5-fluorouracil | en_US |
Subject in Portuguese | Câncer colorretal | en_US |
Subject in Portuguese | Células-tronco | en_US |
Subject in Portuguese | Inibindo Akt/mTOR | en_US |
Title | A novel ruthenium complex with 5-fluorouracil suppresses colorectal cancer stem cells by inhibiting Akt/mTOR signaling | en_US |
Type | Article | en_US |
DOI | 10.1038/s41420-023-01759-6 | |
Abstract | [Ru(5-FU)(PPh3)2(bipy)]PF6 (Ru/5-FU) is a novel ruthenium complex with 5-fluorouracil with promising potential against colorectal cancer (CRC). In the present study, we investigated the molecular mechanism of Ru/5-FU action in HCT116 CRC cells. Ru/5-FU exhibited potent cytotoxicity on a panel of cancer cell lines and on primary cancer cells and induced apoptosis in HCT116 CRC cells. Ru/5-FU reduced AKT1 gene transcripts, as well as the expression of Akt1 and Akt (pS473) and downstream Akt proteins mTOR (pS2448), S6 (pS235/pS236), 4EBP1 (pT36/pT45), GSK-3β (pS9) and NF-κB p65 (pS529), but not Akt upstream proteins Hsp90 and PI3K p85/p55 (pT458/pT199), indicating an inhibitory action of Akt/mTOR signaling. Ru/5-FU increased LC3B expression and reduced p62/SQSTM1 levels, indicating autophagy induction. Curiously, the autophagy inhibitors 3-methyladenine and chloroquine increased Ru/5-FU-induced cell death, indicating an induction of cytoprotective autophagy by this compound. Ru/5-FU also reduced clonogenic survival, as well as the percentage of CD133+ cells and colonosphere formation, indicating that Ru/5-FU can suppress stem cells in HCT116 cells. Ru/5-FU inhibited cell migration and invasion in wound healing assays and Transwell cell invasion assays, along with a reduction in vimentin expression and an increase in E-cadherin levels, indicating that Ru/5-FU can interfere with epithelial-mesenchymal transition. Ru/5-FU also inhibited in vivo HCT116 cell development and experimental lung metastases in mouse xenograft models. Altogether, these results indicate that Ru/5-FU is an anti-CRC chemotherapy drug candidate with the ability to suppress stemness in CRC cells by inhibiting Akt/mTOR signaling. | en_US |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | en_US |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | en_US |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | en_US |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Odontologia. Departamento de Propedêutica. Salvador, BA, Brasil. | en_US |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil . | en_US |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Odontologia. Departamento de Propedêutica. Salvador, BA, Brasil. | en_US |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Centro Universitário SENAI/CIMATEC. Instituto SENAI de Inovação (ISI) em Sistemas Avançados em Saúde. Salvador, BA, Brasil. | en_US |
Affilliation | Hospital São Rafael. Rede D’Or/São Luiz. Salvador, BA, Brasil / Universidade do Estado da Bahia. Salvador, BA, Brasil. | en_US |
Affilliation | Universidade Federal de Ouro Preto. Departamento de Química. Ouro Preto, MG, Brasil. | en_US |
Affilliation | Universidade Federal de São Carlos. Departamento de Química. São Carlos, SP, Brasil. | en_US |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | en_US |
Subject | Ruthenium complex | en_US |
Subject | 5-fluorouracil | en_US |
Subject | Colorectal cancer | en_US |
Subject | Stem cells | en_US |
Subject | Inhibiting Akt/mTOR | en_US |
DeCS | Compostos de rutênio | en_US |
DeCS | Fluoruracila | en_US |
DeCS | Neoplasias colorretais | en_US |
DeCS | Células-tronco | en_US |