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

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.

A decision support system to recommend appropriate therapy protocol for AML patients

“…In conclusion, ENT2 shows potential as a target for developing therapeutics (Naes et al, 2023 ). Elevated levels of ENT2 in the blasts at the time of diagnosis of AML were associated with a lower response to induction therapy (Rodríguez-Macías et al, 2023 ). Moreover, higher ENT2 levels were linked to a poor response to treatment.…”

Effective Prognostic Model for Therapy Response Prediction in Acute Myeloid Leukemia Patients

“…Previously, in our studies related to acute leukemias [ 21 , 22 ], as well as in the works related to a wide range of neoplastic diseases of various histological origins (gastric cancer [ 33 ], renal cancer [ 34 ], colorectal cancer [ 35 ], osteosarcoma [ 36 ]), correlations of the therapy response and the clinical outcome of tumor patients with the drug sensitivity of their tumor cells were demonstrated. As for hematological disorders and particularly AML, many works and reviews show the clinical and prognostic relevance of drug transporter proteins [ 37 , 38 , 39 , 40 , 41 ]. However, in most studies, drug resistance marker characteristics were considered separately.…”