Reversal of LRP-associated drug resistance in colon carcinoma SW-620 cells

Resistance to multiple drugs is mediated by lung resistance-related protein (LRP) as well as P-glycoprotein (P-gp) and multidrug resistance protein (M RP), The levels of expression of LRP mRNA and LRP in a human colon carcinom a cell line, SW-620, were increased by the differentiation-inducing agent, sodium butyrate (NaB), Treatment of SW-620 cells with NaB for 2 weeks confe rred resistance to adriamycin (ADM) and VP-16, The resistance was almost co mpletely reversed by PAK-104P, a pyridine analog, but not by cepharanthine. ADM accumulated mainly in the nuclei of SW-620 cells not treated with NaB and in the cytoplasm of SW-620 cells treated with NaB, When the NaB-treated SW-620 cells were incubated with ADM in the presence of PAK-104P, the accu mulation of ADM in nuclei was substantially increased. Isolated nuclei from untreated cells accumulated more ADM than nuclei from NaB-treated cells. E fflux of ADM from the nuclei isolated from NaB-treated cells was enhanced. PAK-104P and an antibody against LRP increased the accumulation of BDM in t he isolated nuclei from NaB-treated cells, and inhibited the enhanced efflu x of ADM from the nuclei. These findings suggest that at least in part, PAK -104P reverses LRP-mediated drug resistance by inhibiting the efflux of ADM from nuclei. PAK-104P may be useful for reversing MDR in tumors that overe xpress LRP, (C) 2001 Wiley-Liss, Inc.