Abstract
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.
Footnotes
- Received July 8, 1997.
- Accepted August 12, 1997.
-
Send reprint requests to: Dr. Julie K. Horton, Laboratory of Structural Biology, MD F3–01, NIEHS, P.O. Box 12233, T.W. Alexander Drive, Research Triangle Park, NC 27709. E-mail:horton1{at}niehs.nih.gov
-
This work was supported in part by Searle Research and Development; American Heart Association, Texas Affiliate, Grant 966-1613 (G.A.A.); National Institutes of Health Grants CA72783 (G.A.A.), CA23099, and CA21675 (Cancer Center Support grant); and American Lebanese Syrian Associated Charities (P.J.H.); and the Department of Atomic Energy, Government of India (K.N.T.).
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|