In vitro effect of multidrug resistance modifiers on idarubicinol efflux in blasts of acute myeloid leukemia

Abstract

Recent results show that the intracellular uptake pattern of idarubicin (IDA) in multidrug-resistant (MDR) cells is nearly identical to that seen in the drug-sensitive parent cell line, whereas the MDR cells have minimal daunorubicin (DNR) uptake compared with the drug-sensitive parent cells. It is known that the major metabolite of IDA, idarubicinol (IDA-OL), has nearly the same cytotoxicity as IDA, while the cytotoxicity of daunorubicinol (DNR-OL) is about 1/30th of that of DNR. We examined the effect of the MDR modifiers verapamil and dexniguldipine on the efflux of IDA, DNR and their hydroxylated metabolites IDA-OL and DNR-OL in blast populations of acute myeloid leukemia (AML), in the MDR-negative cell line CEM-CCRF and in their MDR-positive counterpart (CEM-VBL). All patients with relapsed or persistent AML had been pretreated with IDA and cytosine arabinoside. The efflux of the anthracyclines was estimated by flow cytometry. A total of 36 patients with AML were investigated; 18 out of 36 AML blast populations showed an efflux of DNR, DNR-OL and IDA-OL. The efflux of DNR, DNR-OL and particularly IDA-OL could be reversed by 10 microM verapamil or 1 microM dexniguldipine. For IDA we found an effusion of 40 +/- 11% in all blast populations which could not be significantly inhibited by the modulators. Similar results for IDA were found in the MDR-positive cell line (CEM-VBL 100) and in their MDR-negative counterpart (CEM-CCRF). The incubation of CEM-CCRF cells with DNR, DNR-OL, IDA-OL and especially IDA led to MDR induction as determined by reverse transcription/polymerase chain reaction analysis with MDR-specific primer and by cellular efflux studies. We conclude that the outcome of chemotherapy with idarubicin is influenced by MDR, although IDA is not essentially MDR-dependent itself, but because IDA-OL is actively involved in multidrug resistance. Further investigations should consider the question of whether the combination of IDA and MDR modifiers can enhance the serum level of the active metabolite IDA-OL and can reverse the MDR pattern in cells treated with IDA.

Modeling the Metabolism of Idarubicin to Idarubicinol in Rat Heart: Effect of Rutin and Phenobarbital

“…Fourth, the enhancement of the IDOL re-uptake into Compartment 2 by the P-glycoprotein inhibitors verapamil and amiodarone (increase in V max ) is similar to that reported for IDA (Weiss and Kang, 2002). This is in principal accordance with the action of multidrug resistant modulators on IDOL concentration in tumor cells (Schroder et al, 2000;Smeets et al, 2001) and suggests that P-glycoprotein inhibitors may also enhance the cardiac accumulation of IDOL. The physiologic role of cardiac P-glycoprotein expression and pharmacokinetic consequences of P-glycoprotein inhibition have been addressed previously (Weiss and Kang, 2002; and the references cited therein).…”

Cyclosporin increases cellular idarubicin and idarubicinol concentrations in relapsed or refractory AML mainly due to reduced systemic clearance

“…Moreover, our data suggest that ida-ol is more MDR-dependent than IDA. In vitro research with AML blasts by Schroder et al 51 supports this clinical observation. We measured cellular IDA and ida-ol concentrations in the overall cell population.…”

Metabolic carbonyl reduction of anthracyclines — role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents

“…On the other hand, active efflux of IDAol from leukemia cells could be inhibited by MDR modulators, while IDA efflux under the same conditions was not significantly affected [42]. Also, in K562 cells, resistance acquired by ABCB1 transfection affected IDAol activity more than IDA activity [41].…”