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.
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.
Department of Biochemistry, University of Szczecin, 3c Felczaka St, 71-412 Szczecin, Poland.
Dorota
D
Kostrzewa-Nowak
Mark J I
MJ
Paine
Anna
A
Korytowska
Katarzyna
K
Serwatka
Sylwia
S
Piotrowska
C Roland
CR
Wolf
Jolanta
J
Tarasiuk
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D008942:Mitoxantrone / Q000378:metabolism / Q000494:pharmacology*; D009249:NADP / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D010084:Oxidation-Reduction; D013053:Spectrophotometry
D000970:Antineoplastic Agents; D009249:NADP; D004317:Doxorubicin; D008942:Mitoxantrone; D009251:NADPH-Ferrihemoprotein Reductase