Hyperthermic chemotherapy inhibits respiration, glutamate dehydrogenase and increases susceptibility to cisplatin of ovarian cancer cells

Abstract

Hyperthermic chemotherapy is used aiming to overcome the resistance of cancer cells to cisplatin. Mitochondria in tumour cells are dependent on glutamate metabolism and activity glutamate dehydrogenase (GDH). We investigated effects of mild hyperthermia (40°C and 43°C for 1 h), cisplatin or combination of both treatments on GDH activity, respiration and cell viability immediately after hyperthermic treatment (0 h) and after 24 and 48 h recovery at 37°C in ovarian tumour Ovcar-3 cell line. GDH was activated under hyperthermic conditions at starting point (0 h), however in the presence of cisplatin hyperthermia induced opposite effect – GDH activity decreased by 6 and 26% at 40 and 43°C, respectively). After 24 h recovery from hyperthermia GDH activity was reduced in both groups, and GDH inhibition was stronger in cells treated with cisplatin. Inhibitory effect remained after 48 h recovery only in cisplatin treated cells (GDH activity decreased by 61% at 37°C and by more than by 70% after 40 or 43°C hyperthermia. Hyperthermia alone (40°C and 43°C) had no statistically significant effect on respiration as compared to 37°C and did not affect cell survival after 48 h recovery. Pretreatment of cells with cisplatin at hyperthermic conditions (43°C) decreased State 2 and State 3 respiration rates by 28% and 42%, respectively. Combination of hyperthermia and cisplatin reduced cell viability more than cisplatin alone (viability of cisplatin treated cells was 21%, meanwhile combination with both hyperthermic conditions resulted in 10% of viable cells after 48 h). Signs of early apoptosis in hyperthermia alone treated cells appeared after 24 h, but were absent after 48 h. Cisplatin induced early apoptotic signs after 24 and 48 h recovery both under normothermic and hyperthermic conditions. We conclude that hyperthermia enhanced sensitivity of Ovcar-3 cells to cisplatin: [...]