ANTITUMOR EFFECTIVENESS AND MECHANISM OF ACTION OF RUTHENIUM COMPLEXES: PROMISING CANDIDATES FOR NEW CHEMOTHERAPEUTIC

Silveira-Lacerda, E.P. (Universidade Federal de Goiás), Mello, F.M.S (Universidade Federal de Goiás), Carvalho, W.P (Universidade Federal de Goiás), Cardoso, C.G. (Universidade Federal de Goiás), Grisolia, C.K. (Universidade Federal de Goiás), Melo-Reis,

Department of Genetic, Institute of Biological Sciences, Federal University of Goias – UFG, GoiâniaSome cancer types there are no specific therapies, leading to a poorer prognosis associated with invasion and metastases, such as triplo negative breast cancer (TNBC). Ruthenium complexes have emerged as promising candidates in the search for development of new chemotherapeutic metallopharmaceuticals to help overcome the limitations of efficacy and safety of current therapies in cancer, acting in all step involved in the tumor growth and progression. Our previous in vitro studies reported non-genotoxic and non-mutagenic effects of some Ruthenium complexes. Ruthenium(II)/amino acids complexes inhibited growth of cancer cells, in vitro, additionally the Ruthenium(II)/tryptophan complex induced cell death by apoptosis, cell cycle block, and DNA damage in Ehrlich tumor cells (murine breast cancer), but it does not induce DNA damage in non-tumor cells. Recently, in vivo study demonstrated that the Ruthenium(II)/methionine and Ruthenium(II)/tryptophan complexes inhibit the peritoneal carcinomatosis progression in Swiss mice, leading to reduce tumor growth and increase mean survival time with less toxicity than cisplatin. These same complexes demonstrated low toxicity against the rodent and zebrafish models, showing low acute oral toxicity in mice without mortality and behavioral changes, leading to mild nephrotoxicity. In a short-term exposure, these complexes showed, in therapeutic doses, a lack of mutagenicity and low genotoxicity in rodent model, with less mutagenicity and genotoxicity than cisplatin. These complexes have low toxicity to zebrafish embryos, but in high concentrations causes malformation in zebrafish development, and the Ruthenium(II)/tryptophan complex leads the high mortality. In this study, we investigated the effects of the Ruthenium(II)/methionine and Ruthenium(II)/tryptophan complexes in the inducing of cell death, and inhibition of migration, clonogenic survival ability and metastasis of MDA-MB-231 cells (human TNBC). Besides cytotoxicity, these complexes inhibited the clonogenic survival and migration abilities of MDA-MB-231 cells. Moreover, these complexes induced apoptosis in MDA-MB-231 cells by increase in number of Annexin V-positive cells, morphological changes and loss of mitochondrial membrane potential. Thus, Ruthenium(II)/methionine and Ruthenium(II)/tryptophan complexes are more active for tumor cells, and their mechanism of action are related with inhibiting clonogenic survival and migration of MDA-MB-231 cells, induction cell cycle block, DNA damage, and mitochondrial membrane potential, lead to p53-mediated apoptosis.apoptosis, DNA damage, in vivo, Ruthenium, toxicity

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