Sequential gene expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and lung resistance protein: functional activity of P-gp and MRP present in the doxorubicin-resistant human K562 cell lines

Previous studies have reported that P-glycoprotein (P-gp), a transmembrane efflux pump involved in multidrug resistance (MDR), was overexpressed in th e doxorubicin (Dox)-resistant human erythroleukemia cell line K562. Neverth eless, several results suggested that P-gp was not the only mechanism invol ved in these resistant cells. Sequential co-expression of other Mon-associa ted proteins was sometimes reported, as MDR-associated protein (MRP) and lu ng resistance protein (LRP), in different MDR cell lines. Thus, mRNA expres sion and stability of P-gp, MRP and LRP were analyzed, while their correspo nding protein levels were quantified in correlation with functional assay, in the K562 cell line and two Dox-resistant variants (K562/R). Their P-gp c ontent was in accordance with their degree of resistance, but not as much i n the level of mRNA expression, suggesting a posttranscriptional regulation . On the other hand, MRP could play a minor role in Mon because of an uncha nged expression in K562/R sublines. A surprising progressive disappearance of LRP in both resistant cells suggested that the original mechanism of dru g redistribution may be operative, involving a negative role for LRP. [(C) 2001 Lippincott Williams & Wilkins].