The Role of Drug Efflux Pumps in Acute Myeloid Leukemia

Abstract

A major problem in the treatment of patients with acute myeloid leukemia (AML) is the occurrence of resistance to structurally and functionally unrelated chemotherapeutic agents, called multidrug resistance (MDR). One of the known MDR mechanisms is the overexpression of adenosine triphosphate (ATP)-dependent efflux pumps. Permeability-glycoprotein (P-gp), the best characterized of the human drug efflux pumps, has been shown to be associated with poor treatment outcome in AML patients. Besides P-gp, in addition the multidrug resistance protein 1 (MRP1) appeared to contribute to the observed resistance in AML. Alternative transporter proteins, such as the MRP1 homologues MRP2, MRP3, MRP5 and MRP6, and the breast cancer resistance protein (BCRP), have been shown to be expressed at variable levels in AML patient cells. The latter proteins have been described to confer resistance to chemotherapeutic agents, such as daunorubicin, mitoxantrone, etoposide and 6-mercaptopurine, which are generally used in the treatment of AML patients; however, they have not yet proven to play a role in drug resistance in AML. The present review gives an overview of the current knowledge concerning these drug transporters, with a focus on the role of the transporter proteins in AML.