The role of oxygen-derived free radicals in the cytotoxicity of doxorubicin in multidrug resistant and sensitive human ovarian cancer cells.

The role of oxygen-derived free radicals in the cytotoxicity of doxorubicin (Dox) was studied in a Dox sensitive human ovarian cancer cell line (A2780) and its multidrug resistant counterpart (2780AD) using reactive oxygen scavengers. In both cell lines, a significant inhibition of Dox toxicity was found after treatment with the hydroxyl radical scavengers, N-acetylcysteine, sodium benzoate and dimethyl sulfoxide, but not with mannitol. The protection was similar in sensitive and resistant cells: 13-39% less growth inhibition was found at Dox concentrations of 0.2 and 0.5 microM for A2780 as well as at 20 and 50 microM for 2780AD. This protection was not due to effects of the scavengers on Dox accumulation, as shown by uptake experiments with radio-labelled Dox. The superoxide anion free radical scavenger ascorbic acid or the enzyme superoxide dismutase as well as the hydrogen peroxide scavenger catalase did not protect cells against Dox-induced cell growth inhibition. Preloading the cells with the enzymes, a treatment which resulted in a two to nine-fold increase in their cellular contents, was not effective either. It is concluded that hydroxyl radicals, but not superoxide anion or hydrogen peroxide likely play a role in the antitumor activity of Dox in sensitive and resistant human ovarian cancer cells.