Effect of organic isothiocyanates on the P-glycoprotein- and MRP1-mediated transport of daunomycin and vinblastine.

Abstract

Organic isothiocyanates (ITCs), or mustard oils, are non-nutrient components present in the diet, especially in cruciferous vegetables. The purpose of this investigation was to examine the effect of ITCs on P-glycoprotein (P-gp)- and multidrug resistance-associated Protein (MRP1)-mediated transport in multidrug resistant (MDR) human cancer cell lines. The direct effect of ITCs on the 2-h cellular accumulation of daunomycin (DNM) and vinblastine (VBL), substrates for both P-gp and MRP1, were measured in sensitive and resistant MCF-7 cells and in PANC-1 cells. Resistant MCF-7 cells (MCF-7/ADR) overexpress P-gp whereas PANC-1 cells overexpress MRP1. The following compounds were evaluated: allyl-, benzyl-(BITC), hexyl-, phenethyl-(PEITC), phenyl-, 1-naphthyl-(NITC), phenylhexyl-, phenylpropyl-, and phenylbutyl-ITC, sulforaphane, erucin, and erysolin. NITC significantly increased the accumulation of DNM and VBL in both resistant cell lines, but had no effect on DNM accumulation in sensitive MCF-7 cells. VBL accumulation in resistant MCF-7 cells was increased 40-fold by NITC whereas that in PANC-1 cells was increased 5.5-fold. Significant effects on the accumulation of DNM and VBL in resistant MCF-7 cells were also observed with benzyl-isothiocyanate whereas PEITC, erysolin, phenylhexyl-ITC, and phenylbutyl-ITC increased the accumulation of DNM and/or VBL in PANC-1 cells. Overall, the inhibitory activities of these compounds in MCF-7 cells and PANC-1 cells were significantly correlated (r2 = 0.77 and 0.86 for DNM and VBL, respectively). Significant effects on accumulation were generally observed with the ITCs at 50 microM concentrations, but not at 10 microM concentrations. One strategy to enhance the effectiveness of cancer chemotherapy is to reverse the MDR phenomena. Our results indicate that certain dietary ITCs inhibit the P-gp- and the MRP1-mediated efflux of DNM and VBL in MDR cancer cells and suggest the potential for diet-drug interactions.