Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells
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Cinara O. D’Sousa Costa1,*, João H. Araujo Neto2,*, Ingrid R.S. Baliza1, Rosane B. Dias1, Ludmila de F. Valverde1, Manuela T.A. Vidal1, Caroline B.S. Sales3, Clarissa A.G. Rocha1, Diogo R.M. Moreira1, Milena B.P. Soares1,4, Alzir A. Batista2 and Daniel P. Bezerra1
1Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
2Department of Chemistry, Federal University of São Carlos, São Carlos, São Paulo, 13561-901, Brazil
3Department of Biomorphology, Institute of Health Sciences, Federal University of Bahia, Salvador, Bahia, 40110-902, Brazil
4Center of Biotechnology and Cell Therapy, Hospital São Rafael, Salvador, Bahia, 41253-190, Brazil
*These authors have contributed equally to this work
Daniel P. Bezerra, email: [email protected]
Keywords: piplartine; piperlongumine; ruthenium complexes; ROS; apoptosis
Received: May 01, 2017 Accepted: September 29, 2017 Published: November 01, 2017
Piplartine (piperlongumine) is a plant-derived molecule that has been receiving intense interest due to its anticancer characteristics that target the oxidative stress. In the present paper, two novel piplartine-containing ruthenium complexes [Ru(piplartine)(dppf)(bipy)](PF6)2 (1) and [Ru(piplartine)(dppb)(bipy)](PF6)2 (2) were synthesized and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes are more potent than metal-free piplartine in a panel of cancer cell lines on monolayer cultures, as well in 3D model of cancer multicellular spheroids formed from human colon carcinoma HCT116 cells. Mechanistic studies uncovered that the complexes reduced the cell growth and caused phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase-3 activation and loss of the mitochondrial transmembrane potential on HCT116 cells. Moreover, the pre-treatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced the complexes-induced apoptosis, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. Treatment with the complexes also caused a marked increase in the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide anion and nitric oxide, and decreased reduced glutathione levels. Application of N-acetyl-cysteine, an antioxidant, reduced the ROS levels and apoptosis induced by the complexes, indicating activation of ROS-mediated apoptosis pathway. RNA transcripts of several genes, including gene related to the cell cycle, apoptosis and oxidative stress, were regulated under treatment. However, the complexes failed to induce DNA intercalation. In conclusion, the complexes are more potent than piplartine against different cancer cell lines and are able to induce caspase-dependent and mitochondrial intrinsic apoptosis on HCT116 cells by ROS-mediated pathway.
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