Yan Ji1, Marilyn E Morris. 1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York at Buffalo, Amherst, New York 14260, USA.
Abstract
PURPOSE: To investigate the effect of organic isothiocyanates (ITCs), dietary compounds with chemopreventive activity, on breast cancer resistance protein (BCRP)-mediated transport. METHODS: The effect of 12 ITCs on the cellular accumulation of mitoxantrone (MX) was measured in both BCRP-overexpressing and BCRP-negative human breast cancer (MCF-7) and large cell lung carcinoma (NCI-H460) cells by flow cytometric analysis. The ITCs showing activity in MX accumulation were examined for their effect on MX cytotoxicity, and the intracellular accumulation of radiolabeled phenethyl isothiocyanate (PEITC) was measured in both BCRP-overexpressing and BCRP-negative NCI-H460 cells. RESULTS: ITCs significantly increased MX accumulation and reversed its cytotoxicity in resistant cells, but had a small or no effect in sensitive cells. The effects of ITCs on MX accumulation and cytotoxicity were ITC-concentration dependent. Significant increases in MX accumulation were observed at ITC concentrations of 10 or 30 microM, and significant reversal of MX cytotoxicity was generally observed at ITC concentrations of 10 microM. Intracellular accumulation of radiolabeled PEITC in BCRP-overexpressing cells was significantly lower than that in BCRP-negative cells and was increased significantly by the BCRP inhibitor fumitremorgin C (FTC). CONCLUSIONS: Certain ITCs are BCRP inhibitors and PEITC and/or its cellular metabolite(s) may represent BCRP substrates, suggesting the potential for diet-drug interactions.
PURPOSE: To investigate the effect of organic isothiocyanates (ITCs), dietary compounds with chemopreventive activity, on breast cancer resistance protein (BCRP)-mediated transport. METHODS: The effect of 12 ITCs on the cellular accumulation of mitoxantrone (MX) was measured in both BCRP-overexpressing and BCRP-negative humanbreast cancer (MCF-7) and large cell lung carcinoma (NCI-H460) cells by flow cytometric analysis. The ITCs showing activity in MX accumulation were examined for their effect on MXcytotoxicity, and the intracellular accumulation of radiolabeled phenethyl isothiocyanate (PEITC) was measured in both BCRP-overexpressing and BCRP-negative NCI-H460 cells. RESULTS: ITCs significantly increased MX accumulation and reversed its cytotoxicity in resistant cells, but had a small or no effect in sensitive cells. The effects of ITCs on MX accumulation and cytotoxicity were ITC-concentration dependent. Significant increases in MX accumulation were observed at ITC concentrations of 10 or 30 microM, and significant reversal of MXcytotoxicity was generally observed at ITC concentrations of 10 microM. Intracellular accumulation of radiolabeled PEITC in BCRP-overexpressing cells was significantly lower than that in BCRP-negative cells and was increased significantly by the BCRP inhibitor fumitremorgin C (FTC). CONCLUSIONS: Certain ITCs are BCRP inhibitors and PEITC and/or its cellular metabolite(s) may represent BCRP substrates, suggesting the potential for diet-drug interactions.
Authors: P Skehan; R Storeng; D Scudiero; A Monks; J McMahon; D Vistica; J T Warren; H Bokesch; S Kenney; M R Boyd Journal: J Natl Cancer Inst Date: 1990-07-04 Impact factor: 13.506
Authors: P K Smith; R I Krohn; G T Hermanson; A K Mallia; F H Gartner; M D Provenzano; E K Fujimoto; N M Goeke; B J Olson; D C Klenk Journal: Anal Biochem Date: 1985-10 Impact factor: 3.365
Authors: C M F Kruijtzer; J H Beijnen; H Rosing; W W ten Bokkel Huinink; M Schot; R C Jewell; E M Paul; J H M Schellens Journal: J Clin Oncol Date: 2002-07-01 Impact factor: 44.544