Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells.

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dc.contributor.authorBomfim, Larissa Mendes
dc.contributor.authorAraujo, Fênix Alexandra de
dc.contributor.authorDias, Rosane Borges
dc.contributor.authorSales, Caroline Brandi Schlaepfer
dc.contributor.authorRocha, Clarissa Araújo Gurgel
dc.contributor.authorCorrea, Rodrigo de Souza
dc.contributor.authorSoares, Milena Botelho Pereira
dc.contributor.authorBatista, Alzir Azevedo
dc.contributor.authorBezerra, Daniel Pereira
dc.date.accessioned2020-06-18T17:25:03Z
dc.date.available2020-06-18T17:25:03Z
dc.date.issued2019
dc.description.abstractRuthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)2(PPh3)2] (1) and [Ru(6m2tu)2(dppb)] (2) (where PPh3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate in vitro cellular underlying mechanism and in vivo effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex 1 also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates.pt_BR
dc.identifier.citationBOMFIM, L. M. et al. Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells. Scientific Reports, v. 9, n. 11483, ago. 2019. Disponível em: <https://www.nature.com/articles/s41598-019-47914-x>. Acesso em: 10 fev. 2020.pt_BR
dc.identifier.doihttps://doi.org/10.1038/s41598-019-47914-xpt_BR
dc.identifier.issn2045-2322
dc.identifier.urihttp://www.repositorio.ufop.br/handle/123456789/12372
dc.language.isoen_USpt_BR
dc.rightsabertopt_BR
dc.rights.licenseThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Fonte: o próprio artigo.pt_BR
dc.titleRuthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells.pt_BR
dc.typeArtigo publicado em periodicopt_BR
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