Role of MRP-1 and GST-Pi in MDR and their inhibition by indomethacin in AML

Abstract

Background: MDR continues to be a major challenge to effective chemotherapeutic interventions against cancer. Defining major factor contributing to MDR and inhibiting their action may thus be used for reversing MDR.

Aim: This work aimed to evaluate the role played by MRP-1 and GST-Pi in MDR, and to explore the possible role of indomethacin as an inhibitor of chemotherapy resistance in patients with AML.

Subjects and methods: The study included 2 groups, one included 20 healthy volunteers and the second included 50 AML patients. All patients received one cycle of standard induction chemotherapy, then regrouped according to their response to either CR group or unremitted group. Unremitted patients received a second cycle of chemotherapy combined with indomethacin. From each subject a blood sample was drawn before and after the 1st cycle of chemotherapy and after the 2nd cycle. From blood, mononuclear cells were separated, mRNA was extracted, and RT-PCR was carried out to detect GST-Pi and MRP-1 gene expression.

Results: GST-Pi expression in CR group was 60% before therapy that significantly decreased to 30% after therapy. While in unremitted group, its expression significantly increased from 30% before to 80% after therapy. GST-Pi positive patients had a significantly lower overall and disease free survival time than GST Pi negative patients (P = 0.000 and 0.039, respectively). While MRP-1 expression was so low (20%) and remained unchanged after therapy in both groups. MRP-1 expression did not affect overall or disease free survival. Taking indomethacin with 2nd cycle of chemotherapy in unremitted patients resulted in a significant inhibition of GST-Pi expression and a significantly longer overall survival time than those taking 2nd cycle chemotherapy alone (P =0.034).

Conclusion: MRP-1 is not likely to contribute to MDR, while GST-Pi might have a role in MDR phenotype in AML patients. Furthermore, GST-Pi inhibition significantly reduced MDR in AML patients.

Keywords: AML; MDR; GST-Pi; MRP-1; Indomethacin; RT-PCR