Tseng Elaine, Kamath Amrita, Morris Marilyn E
Pharm Res. 2002 Oct;19(10):1509-15. doi: 10.1023/a:1020460700877.
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.
有机异硫氰酸盐（ITCs），即芥子油，是饮食中存在的非营养成分，尤其是在十字花科蔬菜中。本研究的目的是检测ITCs对多药耐药（MDR）人癌细胞系中P-糖蛋白（P-gp）和多药耐药相关蛋白（MRP1）介导的转运的影响。
在敏感和耐药的MCF-7细胞以及PANC-1细胞中，检测ITCs对柔红霉素（DNM）和长春碱（VBL）2小时细胞内蓄积的直接影响，DNM和VBL是P-gp和MRP1的底物。耐药的MCF-7细胞（MCF-7/ADR）过表达P-gp，而PANC-1细胞过表达MRP1。评估了以下化合物：烯丙基、苄基-（BITC）、己基、苯乙基-（PEITC）、苯基、1-萘基-（NITC）、苯己基、苯丙基和苯丁基-ITC、萝卜硫素、山嵛菜碱和异山嵛菜碱。
NITC显著增加了两种耐药细胞系中DNM和VBL的蓄积，但对敏感MCF-7细胞中DNM的蓄积没有影响。NITC使耐药MCF-7细胞中VBL的蓄积增加了40倍，而在PANC-1细胞中增加了5.5倍。苄基异硫氰酸盐对耐药MCF-7细胞中DNM和VBL的蓄积也有显著影响，而PEITC、异山嵛菜碱、苯己基-ITC和苯丁基-ITC增加了PANC-1细胞中DNM和/或VBL的蓄积。总体而言，这些化合物在MCF-7细胞和PANC-1细胞中的抑制活性显著相关（DNM和VBL的r2分别为0.77和0.86）。通常在50 microM浓度的ITCs下观察到对蓄积的显著影响，但在10 microM浓度下未观察到。
增强癌症化疗效果的一种策略是逆转MDR现象。我们的结果表明，某些膳食ITCs抑制MDR癌细胞中P-gp和MRP1介导的DNM和VBL外排，并提示饮食与药物相互作用的可能性。
