Author | Neves, Sara Parente | |
Author | Carvalho, Nanashara Coelho de | |
Author | Silva, Monize Martins da | |
Author | Rodrigues, Ana Carolina Borges da Cruz | |
Author | Bomfim, Larissa Mendes | |
Author | Dias, Rosane Borges | |
Author | Sales, Caroline Brandi Schlaepfer | |
Author | Rocha, Clarissa Araújo Gurgel | |
Author | Soares, Milena Botelho Pereira | |
Author | Batista, Alzir Azevedo | |
Author | Bezerra, Daniel Pereira | |
Access date | 2019-08-12T12:18:54Z | |
Available date | 2019-08-12T12:18:54Z | |
Document date | 2019 | |
Citation | NEVES, Sara Parente et al. Ruthenium Complexes Containing Heterocyclic Thioamidates Trigger Caspase-Mediated Apoptosis Through MAPK Signaling in Human Hepatocellular Carcinoma Cells. Frontiers in Oncology, v. 9, p. 1-18, 2019. | pt_BR |
ISSN | 2234-943X | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/34705 | |
Sponsorship | Brazilian agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB), and Fundação de Amparo à Pesquisa do
Estado de São Paulo (FAPESP). | pt_BR |
Language | eng | pt_BR |
Publisher | Frontiers Media | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | Complexos de rutênio | pt_BR |
Subject in Portuguese | Tioamidatos heterocíclicos | pt_BR |
Subject in Portuguese | Apoptose | pt_BR |
Subject in Portuguese | ERK1/2 | pt_BR |
Subject in Portuguese | HepG2 | pt_BR |
Title | Ruthenium Complexes Containing Heterocyclic Thioamidates Trigger Caspase-Mediated Apoptosis Through MAPK Signaling in Human Hepatocellular Carcinoma Cells | pt_BR |
Type | Article | pt_BR |
DOI | 10.3389/fonc.2019.00562 | |
Abstract | Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF6 (1), [Ru(tzdt)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3) and [Ru(mpca)(bipy)(dppb)]PF6 (4) were investigated for their cellular and molecular effects in cancer cell lines. Complexes 1 and 2 were the most potent of the four compounds against a panel of different cancer cell lines in monolayer cultures and showed potent cytotoxicity in a 3D model of multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both complexes were able to bind to DNA in a calf thymus DNA model. Compared to the controls, a reduction in cell proliferation, phosphatidylserine externalization, internucleosomal DNA fragmentation, and the loss of the mitochondrial transmembrane potential were observed in HepG2 cells that were treated with these complexes. Additionally, coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death through apoptosis occurred via a caspase-dependent pathway. Moreover, these complexes also induced the phosphorylation of ERK1/2, and coincubation with an MEK inhibitor (U0126), which is known to inhibit the activation of ERK1/2, but not JNK/SAPK and p38 MAPK inhibitors, reduced the complexes-induced apoptosis compared to that in the negative controls, indicating that the induction of apoptotic cell death occurred through ERK1/2 signaling in HepG2 cells. On the other hand, no increase in oxidative stress was observed in HepG2 cells treated with the complexes, and the complexes-induced apoptosis was not reduced with coincubation with the antioxidant N-acetylcysteine or a p53 inhibitor compared to that in the negative controls, indicating that apoptosis occurred via oxidative stress- and p53-independent pathways. Finally, these complexes also reduced the growth of HepG2 cells that were engrafted in C.B-17 SCID mice compared to that in the negative controls. These results indicated that these complexes are novel anticancer drug candidates for liver cancer treatment. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Federal University of São Carlos. Department of Chemistry. São Carlos, SP, Brazil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Federal University of Bahia. Institute of Health Sciences. Department of Biomorphology. Salvador, BA, Brazil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Affilliation | Federal University of São Carlos. Department of Chemistry. São Carlos, SP, Brazil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | pt_BR |
Subject | Ruthenium complexes | pt_BR |
Subject | Heterocyclic thioamidates | pt_BR |
Subject | Apoptosis | pt_BR |
Subject | ERK1/2 | pt_BR |
Subject | HepG2 | pt_BR |