Organic Isothiocyanates: Dietary Modulators of Doxorubicin Resistance in Breast Cancer
Final rept. 1 Jun 2000-31 May 2004
STATE UNIV OF NEW YORK AT BUFFALO AMHERST
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Drug resistance is the main cause for therapeutic failure and death in breast cancer. Our goal is to evaluate dietary organic isothiocyanates ITCs as inhibitors of MDR. Our studies have demonstrated that phenethyl ITC PEITC, benzyl ITC BITC and naphthyl ITC NITC can inhibit P-glycoprotein-, Multidrug Resistance-associated protein MRPl- and Breast Cancer Resistance Protein BCRP-mediated efflux, in cell lines that overexpress these transport proteins. Studies evaluating the mechanism of this interaction have suggested that PEITC is an inhibitor, but not a substrate for P-gp. PEITC represents a substrate for BCRP, and alters MRPl-mediated transport through binding interactions, as well as depletion of the cofactor for transport, glutathione. HPLC assays have been developed to determine the concentrations of these ITOs in biological samples, and a novel LCMSMS assay developed for PEITC, in order to obtain the needed specificity and sensitivity for in vivo studies. The stability and pharmacokinetics of NITC and PEITC have been determined for the first time. These studies represent the first report of inhibition of the ABC efflux proteins, P-glycoprotein, MRPl and BCRP, which are important determinants of MDR. The ITCs may represent a new class of inhibitors of MDR in breast cancer.
- Medicine and Medical Research