Structure-activity analysis of taxane-based broad-spectrum multidrug resistance modulators.

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. 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. 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. 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.