Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy

SIMPLE SUMMARY: The impact of genes involved in drug transport and metabolism in regard to the lack of response of acute myeloid leukemia (AML) cells to induction chemotherapy using cytarabine and idarubicin has been investigated in blast cells collected at diagnosis. The aim of this study was to evaluate the usefulness of measuring their expression in order to predict the response to induction chemotherapy. In AML patients with a lower response, the elevated expression of uptake and export transporters and enzymes was found. Additionally, AML cell lines more sensitive to cytarabine showed altered levels of these genes. In conclusion, the poor response of AML patients to chemotherapy can be associated with the increased expression of inactivating enzymes, likely resulting in a reduced intracellular concentration of the active cytarabine metabolite in their blasts. ABSTRACT: Despite its often low efficacy and high toxicity, the standard treatment for acute myeloid leukemia (AML) is induction chemotherapy with cytarabine and idarubicin. Here, we have investigated the role of transporters and drug-metabolizing enzymes in this poor outcome. The expression levels (RT-qPCR) of potentially responsible genes in blasts collected at diagnosis were related to the subsequent response to two-cycle induction chemotherapy. The high expression of uptake carriers (ENT2), export ATP-binding cassette (ABC) pumps (MDR1), and enzymes (DCK, 5-NT, and CDA) in the blasts was associated with a lower response. Moreover, the sensitivity to cytarabine in AML cell lines was associated with ENT2 expression, whereas the expression of ABC pumps and enzymes was reduced. No ability of any AML cell line to export idarubicin through the ABC pumps, MDR1 and MRP, was found. The exposure of AML cells to cytarabine or idarubicin upregulated the detoxifying enzymes (5-NT and DCK). In AML patients, 5-NT and DCK expression was associated with the lack of response to induction chemotherapy (high sensitivity and specificity). In conclusion, in the blasts of AML patients, the reduction of the intracellular concentration of the active metabolite of cytarabine, mainly due to the increased expression of inactivating enzymes, can determine the response to induction chemotherapy.