The clinical usefulness of anthracycline antitumour drugs (e.g. doxorubicin, DOX; daunorubicin, DR; pirarubicin, PIRA) is severely limited by the occurrence of multidrug resistance (MDR) associated with the presence of the membrane transporters (e.g. P-glycoprotein, MRP1, BCRP), responsible for the active export of drugs out of resistant cells. In our recent studies we have evidenced the important role of bioreductive activation of DOX and PIRA by exogenously added NADPH-cytochrome P450 reductase (CPR) and NADPH in cytotoxic activity against human promyelocytic leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of multidrug resistance related to the overexpression of P-glycoprotein(HL60/VINC) or MRP1(HL60/DOX).

The aim of this study was to examine the reductive activation of idarubicin (IDA) by human liver CPR and its impact on increasing the cytotoxic activity against sensitive as well as resistant HL60 cell lines. It was found that the absence of methoxy group in the chromophore part of IDA structure did not disturb the ability of this derivative to undergo reductive activation by CPR with the formation of reactive metabolites. It was evidenced, similarly to results obtained previously for the parent drug DOX that, upon CPR catalysis, IDA underwent only the redox cycling (at low NADPH concentration) or multi-stage chemical transformation (at high NADPH concentration). We have also found, using superoxide dismutase (SOD), that the first stage undergoing according to the mechanism of the redox cycling had the key importance for the metabolic conversion of IDA. Our assays showed that the presence of CPR catalysing only the redox cycling of IDA had no effect in increasing its cytotoxicity against sensitive and MDR tumour cells. In contrast, an important increase in cytotoxic activity of IDA, after their metabolic conversion by CPR, was observed against sensitive HL60 as well as multidrug resistant sublines.

In conclusion: the presented data suggest that the reductive activation of IDA by CPR constitutes a possibility to partially restore the activity of this drug against multidrug resistant tumour cells.

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