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

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.