Ruthenium (II) complex cis-[RuII(ŋ2-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(ŋ2-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.

Ruthenium Complexes as Promising Candidates against Lung Cancer

“…Furthermore, Ru(II)-based compounds, such as the polypyridyl Ru complex Ru47 [61], arrested cell growth in the Sphase. Similar results were also obtained for the arene Ru(II) carbazole-based hydrazone complexes Ru51-53 [(η 6 -benzene) Ru(L) Cl] (L = carbazolone benzhydrazone ligands) [64] (Figure 9), whereas Ru30 [54] and Ru48-49 [62] induced apoptosis and cell cycle arrest of A549 lung cancer cells in the G2/M phase. The cytotoxicity of {[Ru(pipe)(dppb)(bipy)]PF 6 } (pipe = piperonylic acid, dppb = 1,4-bis(diphenylphosphino) butane) (Ru50) on A549 cells has been associated with the induction of cell apoptosis via the intrinsic pathway [63].…”

“…Furthermore, Ru(II)-based compounds, such as the polypyridyl Ru complex Ru47 [61], arrested cell growth in the S-phase. Similar results were also obtained for the arene Ru(II) carbazole-based hydrazone complexes Ru51-53 [(η 6 -benzene) Ru(L) Cl] (L = carbazolone benzhydrazone ligands) [64] (Figure 9), whereas Ru30 [54] and Ru48-49 [62] induced apoptosis and cell cycle arrest of A549 lung cancer cells in the G2/M phase.…”

“…Therefore, agents modulating ROS generation have been designed for clinical cancer therapy. For instance, Ru30 [ 54 ], Ru31–32 [ 55 ], Ru33 [ 56 ], Ru36 [ 57 ], and Ru38 [ 58 ] ( Figure 6 and Figure 7 ) altered the mitochondrial function and generated ROS in lung tumor cells, leading to various adverse effects. [ cis -[Ru(η 2 -O 2 CC 7 H 7 O 2 )(dppm) 2 ]PF 6 ] (dppm = bis(diphenylphosphino)methane) ( Ru30 ), with stability in DMSO monitored by 31P {1H} NMR experiments, showed high cytotoxic activity against Leishmania promastigotes [ 91 , 92 ] and selectively targeted lung target tumor cells [ 54 ], while no toxic effect was observed on normal bronchial epithelial BEAS-2B cells.…”

“…For instance, Ru30 [ 54 ], Ru31–32 [ 55 ], Ru33 [ 56 ], Ru36 [ 57 ], and Ru38 [ 58 ] ( Figure 6 and Figure 7 ) altered the mitochondrial function and generated ROS in lung tumor cells, leading to various adverse effects. [ cis -[Ru(η 2 -O 2 CC 7 H 7 O 2 )(dppm) 2 ]PF 6 ] (dppm = bis(diphenylphosphino)methane) ( Ru30 ), with stability in DMSO monitored by 31P {1H} NMR experiments, showed high cytotoxic activity against Leishmania promastigotes [ 91 , 92 ] and selectively targeted lung target tumor cells [ 54 ], while no toxic effect was observed on normal bronchial epithelial BEAS-2B cells. In addition, the increased ROS levels generated by 3.8 µM Ru30 in A549 lung tumor cells caused oxidative stress, which led to proliferation inhibition, changes in the morphology and organization patterns of the actin cytoskeleton, G2/M phase arrest, apoptosis, changes in the mitochondrial membrane potential, and DNA damage [ 54 ].…”

“…[ cis -[Ru(η 2 -O 2 CC 7 H 7 O 2 )(dppm) 2 ]PF 6 ] (dppm = bis(diphenylphosphino)methane) ( Ru30 ), with stability in DMSO monitored by 31P {1H} NMR experiments, showed high cytotoxic activity against Leishmania promastigotes [ 91 , 92 ] and selectively targeted lung target tumor cells [ 54 ], while no toxic effect was observed on normal bronchial epithelial BEAS-2B cells. In addition, the increased ROS levels generated by 3.8 µM Ru30 in A549 lung tumor cells caused oxidative stress, which led to proliferation inhibition, changes in the morphology and organization patterns of the actin cytoskeleton, G2/M phase arrest, apoptosis, changes in the mitochondrial membrane potential, and DNA damage [ 54 ]. Ru31 [Ru(dip) 2 (SA)] and Ru32 [Ru(dmp) 2 (SA)] (dip = 4,7-diphenyl-1,10-phenanthroline; dmp = 2,9-dimethyl-1,10-phenanthroline; SA = salicylate), two Ru(II) complexes bearing O , O -chelated ligands with low toxicity to BEAS-2B, could also induce apoptosis in A549 cells via caspase family proteins and PARP activation, ROS accumulation, DNA damage, MMP reduction, and Cytochrome c release from mitochondria [ 55 ].…”