Organic Isothiocyanates: Dietary Modulators of Doxorubicin Resistance in Breast Cancer
Abstract
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-mediated efflux in cell lines that overexpress P-gp, as well as in cell lines that overexpress another MDR protein, Multidrug Resistance-associated protein (MRP1). Studies evaluating the mechanism of this interaction have suggested that PEITC is an inhibitor, but not a substrate for P-gp. ITCs inhibit MRP1 through binding interactions, as well as the depletion of the cofactor for transport, glutathione. HPLC assays have been developed to determine the concentrations of these ITCs in biological samples, and a novel LC/MS/MS 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. Both NITC and PEITC exhibit dose-dependent disposition, with clearance decreasing with increasing dose. The bioavailability of PEITC was determined for the first time, and found to be excellent (>80%). The ITCs may represent a new class of inhibitors of MDR in breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2003
- Accession Number
- ADA424671
Entities
People
- Marilyn E. Morris
Organizations
- State University of New York