BACKGROUND: Clinical drug resistance is frequently associated with overexpression of the multidrug resistance (MDR) proteins P-glycoprotein (Pgp), multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP). Taxanes are substrates for Pgp and MRP-1, but not BCRP. Taxane-based reversal agents (tRAs) are non-cytotoxic MDR modulators previously examined for broad-spectrum modulation of Pgp, MRP-1 and BCRP. MATERIALS AND METHODS: Modulation by tRAs was studied by flow cytometry and resistance to taxanes was studied in cytotoxicity assays in the parental HL60/wt, 8226/wt and MCF7/S, and the resistant HL60/ADR, 8226/Dox6, 8226/MR20 and MCF7 AdVp3000 cell lines. Amino acid sequence (BLAST) alignments were performed using ClustalW. RESULTS: Structure-activity analysis demonstrated greatest alignment of BCRP with the transmembrane 7-12 region of Pgp and identified tRA side groups that contributed or were detrimental to modulation. CONCLUSION: Identification of tRA side groups contributing to modulation of Pgp, MRP-1 and BCRP will allow the design of a next generation of tRAs and will optimize their potential clinical applicability.
BACKGROUND: Clinical drug resistance is frequently associated with overexpression of the multidrug resistance (MDR) proteins P-glycoprotein (Pgp), multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP). Taxanes are substrates for Pgp and MRP-1, but not BCRP. Taxane-based reversal agents (tRAs) are non-cytotoxic MDR modulators previously examined for broad-spectrum modulation of Pgp, MRP-1 and BCRP. MATERIALS AND METHODS: Modulation by tRAs was studied by flow cytometry and resistance to taxanes was studied in cytotoxicity assays in the parental HL60/wt, 8226/wt and MCF7/S, and the resistant HL60/ADR, 8226/Dox6, 8226/MR20 and MCF7 AdVp3000 cell lines. Amino acid sequence (BLAST) alignments were performed using ClustalW. RESULTS: Structure-activity analysis demonstrated greatest alignment of BCRP with the transmembrane 7-12 region of Pgp and identified tRA side groups that contributed or were detrimental to modulation. CONCLUSION: Identification of tRA side groups contributing to modulation of Pgp, MRP-1 and BCRP will allow the design of a next generation of tRAs and will optimize their potential clinical applicability.
Authors: Katalin Kovacs; Lina Zhang; Robert S T Linforth; Benjamin Whittaker; Christopher J Hayes; Rupert G Fray Journal: Transgenic Res Date: 2006-11-15 Impact factor: 2.788
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Authors: Theresa Schwarz; Floriane Montanari; Anna Cseke; Katrin Wlcek; Lene Visvader; Sarah Palme; Peter Chiba; Karl Kuchler; Ernst Urban; Gerhard F Ecker Journal: ChemMedChem Date: 2016-03-10 Impact factor: 3.466