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Ruthenium (II) complex cis-[RuII(?2-O2CC7H7O2)(dppm)2]PF6-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity.

ABSTRACT: Ruthenium complexes have been extensively explored as potential molecules for cancer treatment. Considering our previous findings on the remarkable cytotoxic activity exhibited by the ruthenium (II) complex 3-hydroxy-4-methoxybenzoate (hmxbato)-cis-[RuII(?2-O2CC7H7O2)(dppm)2]PF6 against Leishmania promastigotes and also the similar metabolic characteristics between trypanosomatids and tumor cells, the present study aimed to analyze the anticancer potential of hmxbato against lung tumor cells, as well as the partial death mechanisms involved. Hmxbato demonstrated selective cytotoxicity against A549 lung tumor cells. In addition, this complex at a concentration of 3.8 µM was able to expressively increase the generation of reactive oxygen species (ROS) in tumor cells, causing an oxidative stress that may culminate in: (1) reduction in cellular proliferation; (2) changes in cell morphology and organization patterns of the actin cytoskeleton; (3) cell arrest in the G2/M phase of the cell cycle; (4) apoptosis; (5) changes in the mitochondrial membrane potential and (6) initial DNA damage. Furthermore, we demonstrated that the induction of programmed cell death can occur by the intrinsic apoptotic pathway through the activation of caspases. It is also worth highlighting that hmxbato exhibited predominant actions on A549 tumor cells in comparison to BEAS-2B normal bronchial epithelium cells, which makes this complex an interesting candidate for the design of new drugs against lung cancer.

SUBMITTER: Costa MS

PROVIDER: S-EPMC7506019 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Ruthenium (II) complex cis-[RuII(ŋ2-O2CC7H7O2)(dppm)2]PF6-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity.

Costa Mônica Soares MS Gonçalves Yasmim Garcia YG Borges Bruna Cristina BC Silva Marcelo José Barbosa MJB Amstalden Martin Krähenbühl MK Costa Tássia Rafaella TR Antunes Lusânia Maria Greggi LMG Rodrigues Renata Santos RS Rodrigues Veridiana de Melo VM de Faria Franca Eduardo E Zoia Mariana Alves Pereira MAP de Araújo Thaise Gonçalves TG Goulart Luiz Ricardo LR Von Poelhsitz Gustavo G Yoneyama Kelly Aparecida Geraldo KAG

Scientific reports 20200921 1

Ruthenium complexes have been extensively explored as potential molecules for cancer treatment. Considering our previous findings on the remarkable cytotoxic activity exhibited by the ruthenium (II) complex 3-hydroxy-4-methoxybenzoate (hmxbato)-cis-[RuII(ŋ2-O2CC7H7O2)(dppm)2]PF6 against Leishmania promastigotes and also the similar metabolic characteristics between trypanosomatids and tumor cells, the present ...[more]

PMID: 32958783

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Project description:The structure of [IrCl2(C58H51N3P4)]Cl·5.5CH3CN or [IrCl2(NHCHPh)(((dppm)C(N2dppm))-? 3P,C,P)]Cl·5.5CH3CN [3, dppm = bis-(di-phenyl-phos-phino)methane; systematic name: di-chlorido(1,1,3,3,7,7,9,9-octa-phenyl-4,5-di-aza-1,3?5,7?4,9-tetra-phosphanona-3,5-dien-6-yl-?2 P 1,P 9)-(phenyl-methanimine-?N)iridium(III) chloride aceto-nitrile hemihendeca-solvate], resulting from an oxygen-mediated cleavage of a triazeneyl-idene-phospho-rane ligand producing a diazo-methyl-ene-phospho-rane and a nitrene moiety, which in turn rearrange via a Staudinger reaction and a 1,2-hydride shift to the first title complex, involves a six-coordinate IrIII complex cation coordinated by a facial PCP pincer ligand, a benzaldimine and two chlorido ligands. The pincer system features a five- and a seven-membered ring, with the central divalent carbon of the PCP pincer ligand being connected to a phosphine and a diazo-phospho-rane. The chlorido ligands are positioned trans to the central carbon atom and to the phospho-rus donor of the seven-membered ring of the pincer system, respectively. A chloride ion serves as counter-ion for the monocationic complex. The structure of [IrI(C26H22N2P2)(C26H22P2)(C6H7N)]I(I3)·0.5I2·CH3OH·0.5CH2Cl2 or [IrI(NHCHPh)((dppm)C(N2)-? 2P,C)(dppm-? 2P,P')]I(I3)·0.5I2·CH3OH·0.5CH2Cl2 {4, systematic name: (4-diazo-1,1,3,3,-tetra-phenyl-1,3?4-diphosphabutan-4-yl-?P 1)iodido[methyl-enebis(di-phenyl-phosphine)-?2 P,P'](phenyl-methanimine-?N)iridium(III) iodide-triiodide-di-chloro-methane-iodine-methanol (2/2/1/1/2)}, accessed via treatment of the triazeneyl-idene-phospho-rane complex [Ir((BnN3)C(dppm)-? 3P,C,N)(dppm-? 2P,P')]Cl with hydro-iodic acid, consists of a dicationic six-coordinate IrIII complex, coordinated by a bidentate diazo-methyl-ene-phospho-rane, a benzaldimine, a chelating dppm moiety and an iodido ligand. The phospho-rus atoms of the chelating dppm are trans to the central carbon atom of the diazo-methyl-ene-phospho-rane and the iodide ligand, respectively. Both an iodide and a triiodide moiety function as counter-ions. The aceto-nitrile solvent mol-ecules in 3 are severely disordered in position and occupation. In 4, the I3 - anion is positionally disordered (ratio roughly 1:1), as is the I- anion with a ratio of 9:1. The di-chloro-methane solvent mol-ecule lies near a twofold rotation axis (disorder) and was refined with an occupancy of 0.5. Another disorder occurs for the solvent methanol with a 1:1 ratio.

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Ruthenium (II) complex cis-[RuII(?2-O2CC7H7O2)(dppm)2]PF6-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity.

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Ruthenium (II) complex cis-[Ru<sup>II</sup>(ŋ<sup>2</sup>-O<sub>2</sub>CC<sub>7</sub>H<sub>7</sub>O<sub>2</sub>)(dppm)<sub>2</sub>]PF<sub>6</sub>-hmxbato induces ROS-mediated apoptosis in lung tumor cells producing selective cytotoxicity.

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