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Design and antitumor studies on metal-based-complexes against metastatic and/or chemoresistant cells

Abstract

The development of drug resistance remains the main limiting factor for the effectiveness of the treatment of cancer patients. The challenge to overcome resistance is multifaceted and highly complex. The search for new molecules to compose new combination chemotherapy regimens is a very active research area for cancer treatment. Particularly, metal complexes naturally emerge as very interesting candidates as they are capable of acting on multiple targets, inducing different biological effects compared to those of organic drugs. For example, cisplatin and analogues are used in combination with other antitumor drugs to treat nearly 50% of all cancers. This proposal aims to evaluate the antitumor potential of new metal complexes, combined or not with other antitumor drugs, against resistant and/or metastatic tumor lines whose treatment is still very limited.Compounds of the type [MCl(X Y)(PR3)] (M = Pd, Pt; X Y = N,S-chelating thiosemicarbazones, orthometallated amines/imines) and silver complexes [Ag(L)(TSC)]NO3 and [AgCl(PR3)2(TSC)], where PR3 = monodentate phosphines, L = diiminic ligands/hydroxyquinolines and TSC = thiosemicarbazones. The characterization of the new ligands and their complexes will be carried out based on the results obtained by the techniques of elemental analysis, IR and NMR spectroscopy, ESI/MS mass spectrometry, and single crystal X-ray diffraction. The cytotoxic effects and determination of mean inhibitory concentration of the complexes in 2D cultures of sensitive and resistant cell lines will be investigated. The most promising complexes will be selected for further studies on their effects on the action of enzymes associated with resistance mechanisms, such as cathepsins and topoisomerase II, as well as with biomolecules of interest, such as DNA and HSA. The antiproliferative effects of the most promising complexes in the presence of antitumor drugs, such as cisplatin and doxorubicin, will be studied in order to evidence whether there is a synergistic or antagonistic effect between them. The potential for apoptosis/necrosis induction and caspase-3 cleavage mediated by the selected complexes should also be evaluated. The participation of the mitochondria-lysosomes axis in the mechanism of action of these complexes will be investigated, as well as their antiproliferative action in 3D tumor cell cultures. In silico studies should be performed to help understand the possible mechanisms of enzymatic inhibition induced by the compounds. (AU)

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