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Human NADPH-Cytochrome P450 Reductase Overexpression Does Not Enhance the Aerobic Cytotoxicity of Doxorubicin in Human Breast Cancer Cell Lines¹

Department of Pharmacology, Medical Sciences Building, University of Toronto, Toronto, Ontario, M5S 1A8 Canada [S. R., C. L., T. I., D. S. R.], and Auckland Cancer Society Research Centre, University of Auckland, Auckland 1000, New Zealand [A. V. P.]

Doxorubicin is a useful antineoplastic drug with multiple mechanisms of cytotoxicity. One such mechanism involves the reductive bioactivation of the quinone ring to a semiquinone radical, which can exert direct toxic effects and/or undergo redox cycling. We hypothesized that human NADPH-cytochrome P450 reductase (CYPRED) catalyzes doxorubicin reduction and that overexpression of this enzyme sensitizes human breast cancer cell lines to the aerobic cytotoxicity of doxorubicin. cDNA-expressed human CYPRED catalyzed doxorubicin reduction, measured as the rate of doxorubicin-stimulated NADPH consumption. Using a bank of 17 human liver microsomal samples, the rate of doxorubicin reduction correlated with CYPRED catalytic activity and CYPRED protein immunoreactivity. Diphenyliodonium chloride, a mechanism-based inactivator of CYPRED, inhibited CYPRED activity and doxorubicin reduction in human liver microsomes with similar concentration dependence. Stably transfected clones of MDA231 human breast cancer cells overexpressing human CYPRED immunoreactive protein and catalytic activity showed enhanced sensitivity to the aerobic cytotoxicity of tirapazamine, a bioreductive drug known to be activated by CYPRED; however, no sensitization to the cytotoxic effects of doxorubicin was observed. Although human CYPRED is an important catalyst of doxorubicin reduction, overexpression of this enzyme does not confer enhanced sensitivity of human breast cancer cells to the aerobic cytotoxicity of doxorubicin.

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