In vitro and in vivo study of Ru(II)/phosphine complexes with anticancer activities

Abstract

Metal complexes are considered an important resource in the development of anticancer drugs such as cisplatin, which is one of the most commonly agents used in Cancer treatment, with high rate of cure, but with high toxicity to the kidneys and an increasing number of cases of resistance. Compounds based on transition metals have been studied as potential antitumor and antimetastatic agents and among them stand out ruthenium compounds. Thus, studies on the mechanism of action of these complexes become important in order to give some light on their real clinical potential, contributing to the development of a possible new antitumor drug. Breast Cancer is the leading cause of death in Brazil and worldwide. Triple Negative Breast Cancer (TNBC), which does not express hormone receptors, comprises 20% of the Breast Cancer cases and presents relapses within 3 years, approximately. Search and development of new treatments for TNBC with low or no side effects, more effective and with less resistance is important to treat this disease. Preliminary studies reported high cytotoxicity of the ruthenium complexes with general formula [Ru(N-S)(dppe)2]PF6 where dppe = 1,2'-bis (diphenylphosphino)ethane and = N-S are (Hmtz) 2-mercaptothiazoline; (Hmmi) mercapto-1-methylimidazole; (Hdamp) 4,6-diamino-2-mercaptopyrimidine, study the interaction of these with biomolecules (DNA and HSA) and against breast tumor cell line MCF-7 and MDA-MB-231 (TNBC) and a lower cytotoxicity to non-tumor cells. These complexes showed no mutagenic activity by means of the Ames test and the micro core, with and without metabolic activation. Besides inhibiting the enzyme topoisomerase IB activity, which is present in large amount in cancer cells. Therefore, in order to determine the potential of these complexes as antitumor chemotherapeutics and to evaluate the influence of biphosphine, the objectives of this study are based on synthesizing new complexes containing biphosphine dppm (1,1'-bis (diphenylphosphine) methane) and to evaluate the cytotoxicity of these new compounds as well as the compounds containing biphosphine dppe, using triple-negative (MDA-MB-231, human and 4T1, murine) breast cancer cell lines for in vitro and in vivo assays. Studies of the mechanism of cell death using the Propidium Iodide labeling assay will be performed by flow cytometry; mitochondrial membrane potential, cell cycle by flow cytometry and profile of proteins involved in the cell death process by the Western blotting technique. The two most promising compounds will be selected for studies in mice with xenograft breast tumors, using the MDA-MB-231 TN strain in nude mice, and the 4T1 strain in Balb-c mice, evaluating tumor progression and the formation of metastases. (AU)