Reversal of drug resistance in P-glycoprotein-expressing T-cell acute lymphoblastic CEM leukemia cells by copper N-(2-hydroxy acetophenone) glycinate and oxalyl bis (N-phenyl) hydroxamic acid

Abstract

Multiple drug resistance (MDR) represents a major obstacle to successful application of chemotherapy and a basic problem in cancer biology. MDR occurs at the cellular level and is multi-factorial in nature. The multidrug resistance gene, MDR1, and its gene product P-glycoprotein (P-gp) are now well known as an important determinant of MDR. Much effort has been devoted to develop P-gp inhibitors to modulate resistance. However, most of these resistance-modifying agents (RMA) are too toxic at the required doses. Therefore, the development of novel RMAs to overcome MDR represents a major challenge to modern cancer chemotherapy. In the present investigation, we describe the effect of oxalyl bis (N-phenyl) hydroxamic acid (OBPHA) and copper N-(2-hydroxy acetophenone) glycinate (CuNG) on multidrug-resistant P-gp-expressing CEM/ADR5000 T-cell acute lymphoblastic leukemia cells. CuNG, a known depleting agent for glutathione (GSH) and inhibitor of glutathione S-transferase (GST) and multidrug resistance-related protein 1 (MRP1), also inhibited P-gp-mediated doxorubicin accumulation and retention. The resistance-modifying effects of OBPHA were stronger than that of CuNG. Both novel RMAs overcame drug resistance more efficiently than verapamil, a well-known P-gp inhibitor. OBPHA and CuNG exposure resulted in an increased doxorubicin accumulation after 1-3 h incubation by down-regulation of P-gp expression after 24 h incubation. This is a clue that different mechanisms may contribute to modulation of P-gp-mediated drug resistance by these compounds. © 2005 Elsevier Ireland Ltd. All rights reserved.