Hyperthermia enhances sensitivity of Ovcar-3 cells to cisplatin

Abstract

Ovarian cancer is the most common cancer for women. Hyperthermic chemotherapy is used aiming to overcome the resistance of cancer cells to cisplatin and to reduce cisplatin doses. Due to the shift in energy metabolism of certain types of cancer to aerobic glycolysis (Warburg effect), glutamate dehydrogenase (GDH) was suggested as an attractive anticancer target, because mitochondria in cancer cells became producers of non-essential amino acids from tricarboxylic acid (TCA) intermediates and exports excess of citrate to cytosol to support fatty acid synthesis and NADPH production. Given that GDH is an enzyme converting glutamate to TCA intermediate α-ketoglutarate, it acquires an important role in Ovarian cancer cell viability. However, the interaction of GDH with common anticancer drugs as well as changes in GDH activity upon the hyperthermia treatment of cancer cells remained uninvestigated. The aim of this study was to investigate the effects of mild hyperthermia (40°C and 43°C for 1h), cisplatin IC50 or combination of both treatments on GDH activity, respiration and cell viability immediately after hyperthermic treatment (0h) and after 24 and 48h recovery at 37°C in Ovcar-3 cell line. Cisplatin inhibits GDH in Ovcar-3 cells, however not immediately after treatment, but only after 24 or 48h recovery by 40 and 60%, respectively. That possibly indicates to indirect inhibition effect (e.g., effect on GDH expression). Hyperthermia (43°C) in the absence of cisplatin strongly stimulates GDH in Ovcar-3 cells, however this effect is pronounced only immediately after treatment and diminished with time to the levelof control. Combination of cisplatin and temperature had greater (by 10%) effect on GDH activity as compared with cisplatin effect alone, however significant difference only detected at 43°C temperature at 0 and 48h. [...]