RT Journal Article
SR Electronic
T1 Characterization of a Novel Bisacridone and Comparison with PSC 833 as a Potent and Poorly Reversible Modulator of P-Glycoprotein
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 948
OP 957
DO 10.1124/mol.52.6.948
VO 52
IS 6
A1 Julie K. Horton
A1 Kuntebommanahalli N. Thimmaiah
A1 Guillermo A. Altenberg
A1 Ariel F. Castro
A1 Glen S. Germain
A1 G. Krishne Gowda
A1 Peter J. Houghton
YR 1997
UL http://molpharm.aspetjournals.org/content/52/6/948.abstract
AB Novel compounds, composed of two acridone moieties connected by a propyl or butyl spacer, were synthesized and tested as potential modulators of P-glycoprotein (P-gp)-mediated multidrug resistance. The propyl derivative 1,3-bis(9-oxoacridin-10-yl)-propane (PBA) was extremely potent and, at a concentration of 1 μm, increased steady state accumulation of vinblastine (VLB) ≈9-fold in the multidrug-resistant cell line KB8–5. In contrast to the readily reversible effects of VRP and cyclosporin A on VLB uptake and similar to the effects of the cyclosporin analog PSC 833, this modulation by PBA was not fully reversed 6–8 hr after transfer of cells to PBA-free medium. Continuous exposure to 3 μm PBA was nontoxic and could completely reverse VLB resistance in KB8–5 cells. Consistent with its effects on VLB transport, the drug resistance-modulating effect of PSC 833 was significantly more persistent than that of VRP. However, the effect of PBA was, like that of VRP, rapidly reversed once the modulator was removed from the extracellular environment. PBA was able to compete with radiolabeled azidopine for binding to P-gp and to stimulate P-gp ATPase activity. However, both the steady state accumulation of PBA and the rate of efflux of PBA were similar in drug-sensitive KB3–1 and drug-resistant KB8–5 cells, suggesting that this compound is not efficiently transported by P-gp. These results indicate that PBA represents a new class of potent and poorly reversible synthetic modulators of P-gp-mediated VLB transport.