The role of bioreductive activation of antitumour anthracycline drugs in cytotoxic activity against sensitive and multidrug resistant leukaemia HL60 cells

Abstract

Clinical usefulness of anthracyclines belonging to bioreductive antitumour drugs is limited by the occurrence of multidrug resistance (MDR). The aim of this study was to examine the role of structural factors of antitumour anthracycline drugs in the ability to undergo bioreductive activation by NADPH cytochrome P450 reductase (CPR) and determine the impact of this activation on increasing the activity especially in regard to MDR tumour cells. It was evidenced that at high NADPH concentration (500μM) anthracyclines having non-modified quinone structure: doxorubicin (DOX), daunorubicin (DR) and idarubicin (IDA) were susceptible upon CPR catalysis to undergo a multi-stage chemical transformation concerning their chromophore part. Additionally, it was evidenced that the modification of the sugar moiety of DOX did not disturb the susceptibility of the obtained derivative (4′-O-tetrahydropyranyl-doxorubicin, pirarubicin, PIRA) to undergo CPR reductive activation. It was also evidenced that the derivatives having modified quinone groupment (5-iminodaunorubicin, 5-Im-DR) were not able to undergo reductive activation by CPR. The high impact of CPR-dependent reductive activation of anthracycline drugs on increasing the activity in regard to sensitive leukaemia HL60 cell line and its MDR sublines overexpressing P-glycoprotein (HL60/VINC) and MRP1 (HL60/DOX) was evidenced. Furthermore, significant changes in binding manner of activated compounds to naked DNA and cellular nucleus in comparison to their non-activated forms were also observed. It could prevent the export of formed adducts out of the cell by MDR proteins and may explain significant increases in intracellular accumulation of these compounds in HL60/VINC and HL60/DOX cells.