Metforminin Bazı Kemoterapötik İlaçlarla Etkileşmesinin İn Vitro Olarak Değerlendirilmesi

Abstract

Metformin is an oral antidiabetic drug widely used in the treatment of type 2 diabetes mellitus. It is stated that diabetes patients have a higher risk of developing different pathologies including cancer than healthy individuals. There are conflicting studies about commonly used metformin that have different biological properties and when taken with cancer chemotherapeutics, it can increase or reduce the effects of them. In this thesis study, it was aimed to determine the possible interactions of metformin being used together with certain chemotherapeutic drugs [doxorubicin, cisplatin and gemcitabine] that have different mechanisms as in vitro in two different cancer cell lines (HepG2 and Hep2). For this purpose, metformin and cytotoxic drugs were applied to cell lines individually and together. In cells, real-time monitoring of cell viability, apoptosis and cell proliferation has been evaluated. Cell viability and damage was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays. Apoptotic and necrotic cell ratios were determined by fluorescence-activated cell sorting in flow cytometry and real-time cell motions were evaluated at XCELLigence. In the preliminary studies, the doses to be applied (in the Hep2 cell line doxorubicin 100-0.8 μM, cisplatin 100-0.8 μM, gemcitabine 100-0.8 μM, metformin 1-10 mM; in the HepG2 cell line doxorubicin 0.08-3.2x10-3 μM, cisplatin 2.0-0.08 μM, gemcitabine 0.4-0.016 μM, metformin 10-0.04 mM) and the duration of exposure (48 hours) was determined for cytotoxic evaluations. In general, it has been observed that the combination of metformin and cytotoxic drugs may increase the effect of the drugs, in spite of, the differences in the results depending on the method of analysis, the cell line and the dosage applied. In conclusion, the evaluation of the possible interactions between cancer chemotherapeutics and metformin in diabetic cancer patients is important for human health. More extensive mechanistic research is needed in order to demonstrate the exact mechanism of interaction.