Modulation by acrolein and chloroacetaldehyde of multidrug resistance mediated by the multidrug resistance-associated protein (MRP)

Acrolein (AC) and chloroacetaldehyde (CHA) are metabolites of the non-multidrug resistance cytotoxic drugs cyclophosphamide and ifosfamide. It has previously been reported that both metabolites can induce extensive depletion of glutathione (GSH) in vitro and in vivo and that this depletion occurs at drug concentrations in the micromolar range. A link between the function of the multidrug resistance-associated protein (MRP) and the intracellular concentration of GSH has also been demonstrated. To determine whether AC and CHA can modulate the function of MRP by inducing GSH depletion, we used two human lung cancer cell lines overexpressing MRP: the large cell carcinoma cell line COR-L23/R and the adenocarcinoma cell line MOR/R0.4, along with their respective sensitive parental lines, COR-L23/P and MOR/P. We showed that micromolar concentrations of AC and millimolar concentrations of CHA are able to deplete GSH concentrations in the cell lines studied. In addition, concentrations of 50 micrometer AC and 5 mm CHA could completely reverse the daunorubicin (DNR) and vinblastine accumulation deficit present in COR-L23/R and partially reverse the DNR accumulation deficit in MOR/R0.4. In contrast, AC and CHA did not reverse the drug accumulation deficit in the P-glycoprotein-overexpressing lung cancer cell line H69/LX4. The effect of CHA and AC on drug accumulation was related to the GSH depletion, as we found a concentration-dependent relationship between the GSH levels and the reversal of the accumulation deficit for both AC and CHA. To substantiate further this correlation, we increased cellular GSH content in AC- and CHA-treated cells with the GSH ethyl ester. An increase in cellular GSH levels in CHA- and AC-treated COR-L23/R cells was accompanied by a restoration of the DNR accumulation deficit. No significant effect of the GSH ethyl ester was detected on DNR accumulation in COR-L23/P parental cells. In conclusion, treatment with AC or CHA can reverse the drug accumulation deficit of MRP-overexpressing cells, and this effect appears to be mediated by GSH depletion.