Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug‐resistant cells

Abstract

Idarubicin (IDA) is an anthracycline anticancer drug utilized in the treatment of acute leukemias. There are conflicting data published with regard to the cross-resistance of IDA in multidrug-resistant (MDR) cells expressing P-glycoprotein (P-gp). We evaluated the cytotoxicity and cellular accumulation of IDA in a panel of anthracycline-selected MDR cell lines. Leukemia K562/R7 cells and sarcoma MES-SA/Dx5 cells expressing high levels of the MDR1 (ABCB1) gene were resistant to IDA (42-fold and 150-fold, respectively). In both of these cell lines, resistance to IDA was equivalent to that for doxorubicin, the drug used to select for the MDR variants. The P-gp inhibitor PSC 833 (valspodar) at 2 microM completely restored sensitivity to IDA. IDA accumulation was decreased 12-fold in MES-SA/Dx5 cells vs parental cell line, and drug uptake was restored to control levels by PSC 833. Reduced intracellular IDA was correlated with P-gp content by flow cytometry. Experiments in NIH3T3 murine cells transfected with the human MDR1 gene substantiated the findings of cross-resistance to IDA and reversal of resistance by PSC 833. Our data indicate that IDA is a high-affinity substrate for P-gp.

Effective Drug Concentration and Selectivity Depends on Fraction of Primitive Cells

“…We performed the MTT cell proliferation assay for the three HL-60 sublines using drugs either with high affinity to their targets (idarubicin and C-123) or low-specificity cosolvents (DMSO and ethanol) where the variable was the initial number of cells used for plating ( Table 4 ) [ 33 , 62 , 63 ]. The highest inhibitory activity (IC 50 , the concentration required to achieve 50% inhibition of culture proliferation) against HL-60 cells was measured for idarubicin and C-123 ( Table 4 ).…”

Anthracyclines, proteasome activity and multi-drug-resistance

“…MDR can often be attributed to over-expression of the mdr1 gene that codes for an ATP-dependent, transmembrane P-glycoprotein (P-gp) efflux pump pathway, which rapidly exports man structurally un-related drugs from the cell, including anthracyclines [1,2]. …”