Abstract #676: A novel daunorubicin derivative that overcomes MDR1- and MRP1-mediated drug resistance

A major problem with anthracyclines, considered to be the most effective type of anticancer drugs, is the emergence of drug resistance. The well-characterized resistant mechanisms for anthracyclines include overexpression of efflux drug transporters such as multidrug resistance genes (MDR1, ABCB1, or P-glycoprotein) and multidrug resistance-associated proteins (MRP1, or ABCC1), which actively export drugs from the cells and thereby reduce intracellular drug accumulation. We hypothesize that direct modifications on the sugar moiety of anthracyclines would circumvent MDR1 and MRP1 efflux, increase drug concentration in cancer cells, and thus overcome transporter-mediated drug resistance. Several daunorubicin (DNR) derivatives were synthesized and characterized. Compared with the parent compound, one of the derivatives W10250 exhibited higher anticancer activity in both drug-sensitive leukemia cells HL-60 and K562 (MDR1(-) and MRP1(-)) and drug-resistant cells HL-60/ADR (MDR1(-)/MRP1(+)) and K562/DOX (MDR1(+)/MRP1(-)). The IC 50 for W10250 growth inhibition of K562 cells is 5-fold lower than that for DNR (0.02 vs. 0.10 µM), while the IC 50 for W10250 growth inhibition of K562/DOX cells is 250-fold lower than that for DNR (0.034 vs. 8.5 µM). The IC 50 for W10250 growth inhibition of HL-60 cells is 15-fold lower than that for DNR (0.001 vs. 0.015 µM), while the IC 50 for W10250 growth inhibition of HL-60/ADR cells is 3300-fold lower than that for DNR (0.002 vs. 6.6 µM). Drug uptake analysis using FACS assay demonstrated that W10250 abolished MDR1 and MRP1-mediated drug efflux and accumulated high intracellular concentration in the drug-resistance cells HL-60/ADR and K562/DOX. Inhibition of MDR1 and MRP1 by cyclosporine A and MK-571, respectively, supported the notion that this derivative is not a substrate for MDR1 and MRP1. DNR at 50 nM induced G2/M arrest in K562 cells through a well-documented topoisomerase II dependent mechanism, while 50 nM WL250 did not cause G2/M arrest but induced apoptosis, indicating a novel mechanism of action. These data suggest that specific sugar modification of anthracyclines abolish MDR1- and MRP1-mediated drug efflux, increase intracellular drug accumulation, and thus overcome both MDR1- and MRP1-mediated drug resistance in cancer therapy. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 676.