The ruthenium complexes cis-(dichloro)tetramineruthenium(III) chloride and cis-tetraammine(oxalato)ruthenium(III) dithionate overcome resistance inducing apoptosis on human lung carcinoma cells (A549)

Abstract

Lung cancer is one of the leading causes of death in the world, and non-small cell lung carcinoma accounts for approximately 75-85 % of all lung cancers. In the present work, we studied the antitumor activity of the compound cis-(dichloro)tetramineruthenium(III) chloride {cis-[RuCl2(NH3)4]Cl} against human lung carcinoma tumor cell line A549. The present study aimed to investigate the relationship between the expression of MDR1 and CYP450 genes in human lung carcinoma cell lines A549 treated with cisCarboPt, cisCRu(III) and cisDRu(III). The ruthenium-based coordinated complexes presented low cytotoxic and antiproliferative activities, with high IC50 values, 196 (±15.49), 472 (±20.29) and 175 (±1.41) for cisCarboPt, cisCRu(III) and cisDRu(III), respectively. The tested compounds induced apoptosis in A549 tumor cells as evidenced by caspase 3 activation, but only at high concentrations. Results also revealed that the amplification of P-gp gene is greater in A549 cells exposed to cisCarboPt and cisCRu(III) than cisDRu(III). Taken together all these results strongly demonstrate that MDR-1 over-expression in A549 cells could be associated to a MDR phenotype of these cells and moreover, it is also contributing to the platinum, and structurally-related compound, resistance in these cells. The identification and characterization of novel mechanisms of drug resistance will enable the development of a new generation of anti-cancer drugs that increase cancer sensitivity and/or represent more effective chemotherapeutic agents.

Anticancer Ruthenium(III) Complexes and Ru(III)-Containing Nanoformulations: An Update on the Mechanism of Action and Biological Activity

“…Therefore, the overall morphological analysis outcomes provided strong evidence of an apoptosis-inducing activity, in line with several in vitro studies supporting apoptotic events to explain the anticancer properties of different ruthenium derivatives, both in their +2 and +3 oxidation states [47,78,112,140,141,153,[155][156][157][158][159][160][161]. However, also other different molecular pathways can be involved in the cell death process [153].…”

“…Therefore, the overall morphological analysis outcomes provided strong evidence of an apoptosis-inducing activity, in line with several in vitro studies supporting apoptotic events to explain the anticancer properties of different ruthenium derivatives, both in their +2 and +3 oxidation states. [47,78,112,140,141,153,[155][156][157][158][159][160][161] However, also other different molecular pathways can be involved in the cell death process. [153] In fact, in the case of MCF-7 cells treated with the DoHuRu/DOTAP liposomes at IC50 conc., in addition to apoptotic hallmarks, also autophagic vacuoles were clearly detectable, suggesting morphological changes associated with autophagy activation (Figure 9c, inset).…”

Synthesis, Characterization of Ruthenium Compounds and Studies of Biological Effects in MCF-7 Tumors Cell Lines

“…Such bands are similar to those observed by Buyukmurat [22] in his study by IR of the 4-ampy coordinated metals Fe and Zn. In addition, the spectra analysis can observe a displacement of the bands referring to the symmetrical and asymmetric vibrations of the group (NH 2 ) for regions of lower energy.…”

Ruthenium Dendrimers against Human Lymphoblastic Leukemia 1301 Cells

“…Because of their rapid metabolism and increased demand for iron, cancer cells can take up ruthenium instead of iron [17,18]. Moreover, ruthenium atoms can perturb DNA replication in tumor cells, leading to cell death [16][17][18][19][20].…”