Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein

Overexpression of ATP-binding cassette transport proteins, including P-glycoprotein (Pgp), multidrug resistance (MDR) protein (MRP-1), and breast cancer resistance protein (BCRP), is a well-characterized mechanism of MDR in tumor cells. Although the cytotoxic taxanes paclitaxel and docetaxel are substrates for Pgp-mediated efflux, the semisynthetic taxane analogue orataxel inhibits drug efflux mediated by Pgp as well as, as we recently demonstrated, MRP-1 and BCRP. Nevertheless, orataxel is not optimal for development as a clinical MDR modulator because of its cytotoxicity. We sought to identify noncytotoxic taxane-based broad-spectrum modulators from a library of noncytotoxic taxane-based reversal agents (tRAs) designed by eliminating the C-13 side chain of the taxane molecule, which inhibits microtubule depolymerization. Twenty tRAs, selected based on modulation of paclitaxel cytotoxicity in Pgp-overexpressing MDA435/LCC6^mdr1 cells, were studied for modulation of retention and cytotoxicity of substrates of MRP-1 and BCRP as well as Pgp in established cell lines overexpressing each of these transporters. Four tRAs modulated MRP-1 and 17 modulated BCRP in addition to Pgp. The four broad-spectrum tRAs strongly modulated daunorubicin and mitoxantrone efflux and enhanced their cytotoxicity in cell lines overexpressing the three MRPs, decreasing IC₅₀ values by as much as 97%. These tRAs, especially tRA 98006, have promise for development as clinical broad-spectrum MDR modulators and warrant more preclinical analysis to determine pharmacokinetic interactions and efficacy.