Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML)

The transporter protein expressions were analyzed by flow cytometry using their specific antibodies. The protein functionalities were assessed by the uptake of their fluorescence substrates in presence or absence their specific modulators. The drug cytotoxicity was evaluated by MTT test.Zosuquidar completely or partially restored drug sensitivity in all P-gp-expressing leukemia cell lines tested and enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AML blasts with active P-gp. In addition, P-gp inhibition by zosuquidar was found to be more potent than cyclosporine A in cells with highly active P-gp.These in vitro studies suggest that zosuquidar may be an effective adjunct to cytotoxic chemotherapy for AML patients whose blasts express P-gp, especially for older patients.Outcomes for patients with acute myeloid leukaemia (AML), particularly those over age 60 years, have not significantly improved in the past 20 years and conventional cytarabine and anthracycline-based chemotherapy remains the gold standard. Despite the activity of these agents, 20% of patients ≤ 60 years and 50% of older patients fail to achieve remission with these standard agents, and only a small proportion patients have a prolonged disease-free survival [1]. Chemoresistance to standard agents has been shown to be related, in part, to overexpression of P-gp, one of the best characterized multidrug resistance (MDR) ABC proteins. P-gp functions by pumping certain drugs out of cells through an active, energy dependent mechanism [2-4].P-gp expression tends to be increased in older patients with AML and likely contributes to their poor response to induction chemotherapy. Therefore, significant interest has developed in combining modulators that block P-gp-mediated drug efflux with standard chemotherapy regimens. However, randomized trials of P-gp modulators such as cyclosporine A (CsA) and PSC-833 in relapsed or refracto