Effect of Organic Isothiocyanates on the P-Glycoprotein- and MRP1-Mediated Transport of Daunomycin and Vinblastine
Purchase on Springer.com
$39.95 / €34.95 / £29.95*
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.
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 μM concentrations, but not at 10 μM 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.
- I. Pastan and M. M. Gottesman. Multidrug Resistance. Annu.Rev.Med. 42:277-286 (1991).
- D. M. Bradshaw and R. J. Arceci. Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. J.Clin.Oncol. 16:3674-3690 (1998).
- M. Gottesman and I. Pastan. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu.Rev.Biochem. 62:385-427 (1993).
- F. Thiebaut, T. Tsuruo, H. Hamada, M. M. Gottesman, I. Pastan, and M. C. Willingham. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc.Natl.Acad.Sci.USA 84:7735-7738 (1987).
- S. Cole, G. Bhardwaj, J. Gerlach, J. Mackie, C. Grant, K. Almquist, A. Stewart, S. Kurz, A. Duncan, and R. Deeley. Overexpression of a transporter gene in a multidrug resistant human lung cancer cell line. Science 258:1650-1654 (1992).
- G. Kruh, K. Gaughan, A. Godwin, and A. Chan. Expression of MRP in human tissues and adult solid tumor cell lines. J.Natl.Cancer Inst. 87:1256-1258 (1995).
- P. Borst, R. Evers, M. Kool, and J. Wijnholds. A family of drug transporters: the multidrug resistance-associated proteins. J.Natl.Cancer Inst. 92:1295-1302 (2000).
- R. Krishna and L. D. Mayer. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur.J.Pharm.Sci. 11:265-283 (2000).
- Y. Zhang and P. Talalay. Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res. 54: 1976s-1981s (1994).
- A. Kamath and M. Morris. Functional expression of P-glycoprotein in the hepatic canalicular membrane of developing rats. J.Pharm.Sci. 87:300-305 (1998).
- P. Wils, V. Phung-Ba, A. Warnery, D. Lechardeur, S. Raeissi, I. J. Hidalgo, and D. Scherman. Polarized transport of docetaxel and vinblastine mediated by p-glycoprotein in human intestinal epithelial cell monolayers. Biochem.Pharmacol. 48:1528-1530 (1994).
- M. M. Bradford. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal.Biochem. 72:248-254 (1976).
- G. C. Yeh, J. Lopaczynska, C. M. Poore, and J. M. Phang. A new functional role for P-glycoprotein: Efflux pump for benzo(alpha)-pyrene in human breast cancer MCF-7 cells. Cancer Res. 52:6692-6695 (1992).
- D. W. Miller, M. Fontain, C. Kolar, and T. Lawson. The expression of multidrug resistance-associated protein (MRP) in pancreatic adenocarcinoma cell lines. Cancer Lett. 107:301-306 (1996).
- S. Benchimol and V. Ling. P-glycoprotein and tumor progression. J.Natl.Cancer Inst. 86:814-816 (1994).
- M. A. Barrand, T. Bagrij, and S. Y. Neo. Multidrug resistance-associated protein: a protein distinct from P-glycoprotein involved in cytotoxic drug expulsion. Gen.Pharmacol. 28:639-645 (1997).
- K. Buser, F. Joncourt, H. J. Altermatt, M. Bacchi, A. Oberli, and T. Cerny. Breast cancer: Pretreatment drug resistance parameters (GSH-system, ATPase, P-glycoprotein) in tumor tissue and their correlation with clinical and prognostic characteristics. Ann. Oncol. 8:335-341 (1997).
- S. S. Hecht. Chemoprevention of lung cancer by isothiocyanates. Adv.Exp.Med. Biol. 401:1-11 (1996).
- G. J. Kelloff, J. A. Crowell, V. E. Steele, R. A. Lubet, W. A. Malone, C. W. Boone, L. Kopelovich, E. T. Hawk, R. Lieberman, J. A. Lawrence, I. Ali, J. L. Viner, and C. C. Sigman. Progress in cancer chemoprevention: Development of diet-derived chemopreventive agents. J.Nutr. 130:467S-471S (2000).
- L. Gamet-Payrastre, P. Li, S. Lumeau, G. Cassar, M. A. Dupont, S. Chevolleau, N. Gasc, J. Tulliez, and F. Terce. Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells. Cancer Res. 60: 1426-1433 (2000).
- C. Huang, W. Y. Ma, J. Li, S. S. Hecht, and Z. Dong. Essential role of p53 in phenethyl isothiocyanate-induced apoptosis. Cancer Res. 58:4102-4106 (1998).
- A. B. Shapiro and V. Ling. Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur.J.Biochem. 250:130-137 (1997).
- A. B. Shapiro, K. Fox, P. Lam, and V. Ling. Stimulation of P-glycoprotein-mediated drug transport by prazosin and progesterone. Evidence for a third drug-binding site. Eur.J.Biochem 259: 841-850 (1999).
- J. Renes, E. G. de Vries, E. F. Nienhuis, P. L. Jansen, and M. Muller. ATP-and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1. Br.J.Pharmacol. 126:681-688 (1999).
- C. G. Dietrich, R. Ottenhoff, D. R. de Waart, and R. P. Oude Elferink. Role of MRP2 and GSH in intrahepatic cycling of toxins. Toxicology 167:73-81 (2001).
- L. Liebes, C. C. Conaway, H. Hochster, S. Mendoza, S. S. Hecht, J. Crowell, and F.-L. Chung. High-performance liquid chromatography-based determination of total isothiocyanate levels in human plasma: Application to studies with 2-phenethyl isothiocyanate. Anal.Biochem. 291:279-289 (2001).
- M. R. Spitz, C. M. Duphorne, M. A. Detry, P. C. Pillow, C. I. Amos, L. Lei, M. de Andrade, X. Gu, W. K. Hong, and X. Wu. Dietary intake of isothiocyanates: Evidence of a joint effect with glutathione S-transferase polymorphisms in lung cancer risk. Cancer Epidemiol.Biomarkers Prev. 9:1017-1020 (2000).
- B. Zhao, A. Seow, E. J. Lee, W. T. Poh, M. Teh, P. Eng, Y. T. Wang, and W. C. Tan, M. C. Yu, and H. P. Lee. Dietary isothiocyanates, glutathione S-transferase-M1,-T1 polymorphisms and lung cancer risk among Chinese women in Singapore. Cancer Epidemiol.Biomarkers Prev. 10:1063-1067 (2001).
- Y. Zhang. Role of glutathione in the accumulation of anticarcinogenic isothiocyanates and their glutathione conjugates by murine hepatoma cells. Carcinogenesis 21:1175-1182 (2000).
- K. V. Speeg, A. L. Maldonado, J. Liaci, and D. Muirhead. Effect of cyclosporine on colchicine secretion by the kidney multidrug transporter studied in vivo. J.Pharmacol. Exp.Ther. 261:50-55 (1992).
- A. Sparreboom, J. van Asperen, U. Mayer, A. H. Schinkel, J. W. Smit, D. K. Meijer, P. Borst, W. J. Nooijen, J. H. Beijnen, and O. van Tellingen. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc.Natl.Acad.Sci.USA 94:2031-2035 (1997).
- Effect of Organic Isothiocyanates on the P-Glycoprotein- and MRP1-Mediated Transport of Daunomycin and Vinblastine
Volume 19, Issue 10 , pp 1509-1515
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- multidrug resistance
- cancer chemotherapy
- Industry Sectors