RESUMO
Multidrug resistance is a serious problem in modern medicine and the reason for the failure of various therapies. A particularly important problem is the occurrence of multidrug resistance in cancer therapies which affects many cancer patients. Observations on the effect of metformin-a well-known hypoglycemic drug used in the treatment of type 2 diabetes-on cancer cells indicate the possibility of an interaction of this substance with drugs already used and, as a result, an increase in the sensitivity of cancer cells to cytostatics. The aim of this study was to evaluate the effect of metformin on the occurrence of multidrug resistance of breast cancer cells. The MCF-7-sensitive cell line and the MCF-7/DX cytostatic-resistant cell line were used for this study. WST-1 and LDH assays were used to evaluate the effects of metformin and doxorubicin on cell proliferation and viability. The effect of metformin on increasing the sensitivity of MCF-7 and MCF-7/DX cells to doxorubicin was evaluated in an MDR test. The participation of metformin in increasing the sensitivity of resistant cells to the effect of the cytostatic (doxorubicin) has been demonstrated.
Assuntos
Neoplasias da Mama , Proliferação de Células , Citostáticos , Doxorrubicina , Resistencia a Medicamentos Antineoplásicos , Metformina , Humanos , Metformina/farmacologia , Células MCF-7 , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Doxorrubicina/farmacologia , Feminino , Proliferação de Células/efeitos dos fármacos , Citostáticos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Hipoglicemiantes/farmacologiaRESUMO
In the presented work, a series of 22 hybrids of 8-quinolinesulfonamide and 1,4-disubstituted triazole with antiproliferative activity were designed and synthesised. The title compounds were designed using molecular modelling techniques. For this purpose, machine-learning, molecular docking, and molecular dynamics methods were used. Calculations of the pharmacokinetic parameters (connected with absorption, distribution, metabolism, excretion, and toxicity) of the hybrids were also performed. The new compounds were synthesised via a copper-catalysed azide-alkyne cycloaddition reaction (CuAAC). 8-N-Methyl-N-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}quinolinesulfonamide was identified in in silico studies as a potential strong inhibitor of Rho-associated protein kinase and as a compound that has an appropriate pharmacokinetic profile. The results obtained from in vitro experiments confirm the cytotoxicity of derivative 9b in four selected cancer cell lines and the lack of cytotoxicity of this derivative towards normal cells. The results obtained from silico and in vitro experiments indicate that the introduction of another quinolinyl fragment into the inhibitor molecule may have a significant impact on increasing the level of cytotoxicity toward cancer cells and indicate a further direction for future research in order to find new substances suitable for clinical applications in cancer treatment.