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oai:arca.fiocruz.br:icict/347772026-10-20T21:43:05Zcom_icict_1744col_icict_57384

Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling Silva, Suellen Leila Rocha Baliza, Ingrid Rayssa Souza Dias, Rosane Borges Sales, Caroline Brandi Schlaepfer Rocha, Clarissa Araújo Gurgel Soares, Milena Botelho Pereira Correa, Rodrigo de Souza Batista, Alzir Azevedo Bezerra, Daniel Pereira Carcinoma Câncer Colorretal Apoptose Celulas Morte celular Rutênio DOENÇAS [C]::Neoplasias::Neoplasias por Tipo Histológico::Neoplasias Epiteliais e Glandulares::Carcinoma DOENÇAS [C]::Neoplasias::Neoplasias por Localização::Neoplasias do Sistema Digestório::Neoplasias Gastrointestinais::Neoplasias Intestinais::Neoplasias Colorretais FENÔMENOS E PROCESSOS [G]::Fenômenos Fisiológicos Celulares::Morte Celular::Morte Celular Regulada::Apoptose ANATOMIA [A]::Células FENÔMENOS E PROCESSOS [G]::Fenômenos Fisiológicos Celulares::Morte Celular COMPOSTOS QUÍMICOS E DROGAS [D]::Compostos Inorgânicos::Elementos Químicos::Metais Pesados::Rutênio 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). R.S. Correa would like to thank the financial support provided by the CNPq (Grant 403588/2016-2 and 308370/2017-1) and FAPEMIG (APQ-01674-18). Ru(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh3 = triphenylphosphine, Thy = thyminate and bipy = 2,2'-bipyridine) is a potent cytotoxic agent with ability to bind to DNA, inducing caspase-mediated apoptosis in leukemia cells. In this study, we investigated the mechanism underlying the cell death induction by Ru(II)-thymine complex in human colon carcinoma HCT116 cells, as well as its effect in xenograft tumor model. The Ru(II)-thymine complex increased significantly the percentage of apoptotic HCT116 cells. Co-treatment with a JNK/SAPK inhibitor, p38 MAPK inhibitor and MEK inhibitor, which inhibit the activation of ERK1/2, caused a marked reduction of the percentage of complex-induced apoptotic cells. Moreover, the Ru(II)-thymine complex induced an increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182) and phospho-ERK1 (T202/Y204) levels in HCT116 cells. Treatment with the Ru(II)-thymine complex increased significantly the phospho-histone H2AX (S139) expression, a DNA damage marker. The expression of phospho-p53 (S15) and MDM2 were not changed, and the co-treatment with a p53 inhibitor (cyclic pifithrin-α) did not reduce the complex-induced apoptosis in HCT116 cells, indicating that the Ru(II)-thymine complex induces DNA damage-mediated apoptosis by JNK/p38/ERK1/2 via a p53-independent signaling. The Ru(II)-thymine complex (1 and 2 mg/kg/day) also inhibited HCT116 cell growth in a xenograft model, reducing the tumor mass at 32.6-40.1%. Altogether, indicate that the Ru(II)-thymine complex is a promising anti-colon cancer drug candidate. 2019-08-13T17:08:42Z 2019-08-13T17:08:42Z 2019 journal article SILVA, Suellen Leila Rocha et al. Ru(II)-thymine complex causes DNA damage and apoptotic cell death in human colon carcinoma HCT116 cells mediated by JNK/p38/ERK1/2 via a p53-independent signaling. Scientific Reports, v. 9, p. 1-11, 2019. 2045-2322 https://arca.fiocruz.br/handle/icict/34777 10.1038/s41598-019-47539-0 eng open access application/pdf Nature Research