Doxorubicin Resistance Conferred by Selective Enhancement of Intracellular Glutathione Peroxidase or Superoxide Dismutase Content in Human MCF-7 Breast Cancer Cells

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Abstract
To examine the role of doxorubicin-stimulated oxyradical formation in tumor cell killing, we introduced glutathione peroxidase (GSH Px) or superoxide dismutase (SOD) into MCF-7 cells by “scrape loading.” Control cytoplasmic GSH Px and SOD levels increased from (mean ± S.E.) 0.37nmol/min/mg and 0.58 μg SOD/mg, respectively, to 3.99 or 7.63 nmol/min/mg and 1.40 or 1.83 μg SOD/mg after treatment with either 150 or 300 units/ml of GSH Px or 20 or 40mg/ml SOD. Resistance to doxorubicin was cbrrelated with the level of GSH Px introduced into the MCF-7 cells: a one-hour exposure to 1.75 μM doxorubicin decreased the cloning efficiency of control cells loaded with medium alone to 34%, whereas doxorubicin-treated cells augmented with 150 or 300 units/ml of GSH Px had plating efficiencies of 56 or 86%, P < 0.05. Introduction of SOD increased MCF-7 resistance to doxorubicin similarly. The heat-inactivated enzymes were not protective. Cells loaded with GSH Px were also resistant to the redox cycling anticancer quinone mitomycin C but not to the redox inactive analogs 5-iminodaunorubicin and mitoxan-trone. suggesting that amplification of GSH Px or SOD levels can produce doxorubicin resistance in MCF-7 cells.