The role of oxidative stress in the cooperation of parthenolide and etoposide in HL-60 cells.

BACKGROUND

The aim of this study was to determine the effect of sesquiterpene lactone parthenolide on the cytotoxic and pro-oxidative effects of etoposide in HL-60 cells.

METHODS

Cytotoxic effects were determined by incubation of HL-60 cells with various concentrations of examined compounds and combinations thereof, which were then stained with propidium iodide and analyzed using a flow cytometer. To determine the role of oxidative stress in the action of the compounds, co-incubation with N-acetyl-l-cysteine (NAC) and parthenolide and/or etoposide was used and the level of reduced glutathione (GSH) was detected.

RESULTS

Parthenolide significantly enhanced the cytotoxic and pro-apoptotic effects of etoposide. However, in most cases of the combinations of parthenolide and etoposide, their effect was antagonistic, as confirmed by an analysis using the CalcuSyn program. The examined compounds significantly reduced the level of GSH in HL-60 cells. Combination of etoposide at a concentration of 1.2 μM and parthenolide also significantly reduced GSH level. However, in the case of a combination of etoposide at a concentration of 2.5 μM with parthenolide, a significant increase in the level of GSH was obtained compared to compounds acting alone. This last observation seems to confirm the antagonism between the compounds tested.

CONCLUSIONS

Parthenolide did not limit the cytotoxic effect of etoposide in HL-60 cells even in the case of antagonistic interaction. If parthenolide does increase GSH levels in combination with etoposide in the normal hematopoietic cells, it could protect them against the pro-oxidative effects of this anti-cancer drug.