ABSTRACT
The present study evaluated the in vivo antitumor effects and toxicity of a new Ru(II) compound, cis-(Ru[phen]2[ImH]2)2+ (also called RuphenImH [RuC]), against Walker-256 carcinosarcoma in rats. After subcutaneous inoculation of Walker-256 cells in the right pelvic limb, male Wistar rats received 5 or 10mgkg-1 RuC orally or intraperitoneally (i.p.) every 3 days for 13 days. A positive control group (2mgkg-1 cisplatin) and negative control group (vehicle) were also used. Tumor progression was checked daily. After treatment, tumor weight, plasma biochemistry, hematology, oxidative stress, histology, and tumor cell respiration were evaluated. RuC was effective against tumors when administered i.p. but not orally. The highest i.p. dose of RuC (10mgkg-1) significantly reduced tumor volume and weight, induced oxidative stress in tumor tissue, reduced the respiration of tumor cells, and induced necrosis but did not induce apoptosis in the tumor. No clinical signs of toxicity or death were observed in tumor-bearing or healthy rats that were treated with RuC. These results suggest that RuC has antitumor activity through the modulation of oxidative stress and impairment of oxidative phosphorylation, thus promoting Walker-256 cell death without causing systemic toxicity. These effects make RuC a promising anticancer drug for clinical evaluation.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma 256, Walker/drug therapy , Coordination Complexes/pharmacology , Gene Expression Regulation, Neoplastic , Reactive Oxygen Species/agonists , Ruthenium/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Carcinoma 256, Walker/genetics , Carcinoma 256, Walker/metabolism , Carcinoma 256, Walker/pathology , Caspase 3/genetics , Caspase 3/metabolism , Cell Respiration/drug effects , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Drug Evaluation, Preclinical , Injections, Subcutaneous , Male , Necrosis/chemically induced , Necrosis/genetics , Necrosis/metabolism , Oxidative Stress/drug effects , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Ruthenium/chemistry , Tumor Burden/drug effects , Tumor Cells, Cultured , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolismABSTRACT
Mesoionic compounds have shown antitumor and citotoxic activity against different tumor cells lines, which has been attributed to their physical and chemical characteristics. Among these compounds, the 1,3,4-thiadiazolium-2-phenylamine derivatives have been highlighted due to their important anti-melanoma activity. In this work, the effects of three derivatives that belong this class, MI-J, MI-4F and MI-2,4diF, on the oxidative stress parameters were evaluated using rat liver mitochondria. All the derivatives prevented natural and calcium induced oxidation of pyridine nucleotides at lower concentrations (6.5 and 32.5nmol/mg protein). The calcium uptake was inhibited by all the derivatives at higher concentrations (65 and 130nmol/mg protein), whereas the cation efflux was inhibited only by the MI-J (52%) and MI-4F (50%), possibly by inhibiting the formation of the permeability transition pore (PTP) by 100% and 50%, respectively, as observed in the same experimental conditions. MI-2,4diF did not inhibit the mitochondrial permeability transition or calcium efflux. The enzymatic activity of glutathione reductase, glutathione peroxidase and catalase was not affected by any derivative, but superoxide dismutase was inhibited by all the derivatives. MI-J inhibited enzyme activity significantly (85%) at the highest concentration (130nmol/mg protein); on the other hand, their activity was less affected by fluorine derivatives (MI-4F-20% and MI-2,4diF-32%). These results suggest that these derivatives exert antioxidant effects on isolated mitochondria.