Bioreductive activation of mitoxantrone by NADPH cytochrome P450 reductase. Implications for increasing its ability to inhibit the growth of sensitive and multidrug resistant leukaemia HL60 cells

• Published in: Cancer letters Vol. 245; no. 1; pp. 252 - 262
• Main Authors: Kostrzewa-Nowak, Dorota, Paine, Mark J.I, Korytowska, Anna, Serwatka, Katarzyna, Piotrowska, Sylwia, Wolf, C. Roland, Tarasiuk, Jolanta
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 08-01-2007; Elsevier Limited
• Subjects: Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Cell culture; Cell growth; Cell Proliferation - drug effects; Cytotoxicity; Decomposition; Deoxyribonucleic acid; DNA; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzymes; Free radicals; Hematology, Oncology and Palliative Medicine; HL-60 Cells; HL60 human promyelocytic leukaemia; Humans; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Metabolites; Mitoxantrone; Mitoxantrone - metabolism; Mitoxantrone - pharmacology; Multidrug resistance; NADP - metabolism; NADPH cytochrome P450 reductase; NADPH-Ferrihemoprotein Reductase - metabolism; Oxidation-Reduction; Reactive metabolites; Spectrophotometry; Studies; Reactive metabolites; HL60 human promyelocytic leukaemia; Mitoxantrone; NADPH cytochrome P450 reductase; Multidrug resistance
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2006.01.012

Abstract The aim of this study was to examine the role of reductive activation of mitoxantrone (MX) by human liver NADPH cytochrome P450 reductase (CPR) in increasing its ability to inhibit the growth of human promyelocytic sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX). Our assays showed that the reduction of MX by exogenously added CPR in the presence of low NADPH concentration had no effect in increasing its ability to inhibit the growth of sensitive and MDR tumour cells. In contrast, an important increase in antiproliferative activity of MX after its reductive activation by CPR at high NADPH concentration was observed against HL60/VINC as well as HL60/DOX cells.