PT  - JOURNAL ARTICLE
AU  - Marcos M. Pires
AU  - Dana Emmert
AU  - Christine A. Hrycyna
AU  - Jean Chmielewski
TI  - Inhibition of P-Glycoprotein-Mediated Paclitaxel Resistance by Reversibly Linked Quinine Homodimers
AID  - 10.1124/mol.108.050492
DP  - 2009 Jan 01
TA  - Molecular Pharmacology
PG  - 92--100
VI  - 75
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/75/1/92.short
4100  - http://molpharm.aspetjournals.org/content/75/1/92.full
SO  - Mol Pharmacol2009 Jan 01; 75
AB  - P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, has been implicated in multidrug resistance of several cancers as a result of its overexpression. In this work, rationally designed second-generation P-gp inhibitors are disclosed, based on dimerized versions of the substrates quinine and quinidine. These dimeric agents include reversible tethers with a built-in clearance mechanism. The designed agents were potent inhibitors of rhodamine 123 efflux in cultured cancer cell lines that display high levels of P-gp expression at the cell surface and in transfected cells expressing P-gp. The quinine homodimer Q2, which was tethered by reversible ester bonds, was particularly potent (IC50 ≈ 1.7 μM). Further studies revealed that Q2 inhibited the efflux of a range of fluorescent substrates (rhodamine 123, doxorubicin, mitoxantrone, and BODIPY-FL-prazosin) from MCF-7/DX1 cells. The reversibility of the tether was confirmed in experiments showing that Q2 was readily hydrolyzed by esterases in vitro (t½ ≈ 20 h) while demonstrating high resistance to nonenzymatic hydrolysis in cell culture media (t½ ≈ 21 days). Specific inhibition of [125I]iodoarylazidoprazosin binding to P-gp by Q2 verified that the bivalent agent interacted specifically with the drug binding site(s) of P-gp. Q2 was also an inhibitor of verapamil-stimulated ATPase activity. In addition, low concentrations of Q2 stimulated basal P-gp ATPase levels. Finally, Q2 was shown to inhibit the transport of radiolabeled paclitaxel (Taxol) in MCF-7/DX1 cells, and it completely reversed the P-gp-mediated paclitaxel resistance phenotype. The American Society for Pharmacology and Experimental Therapeutics