Characterization of a Novel Bisacridone and Comparison with PSC 833 as a Potent and Poorly Reversible Modulator of P-Glycoprotein

  1. Julie K. Horton1,2,
  2. Kuntebommanahalli N. Thimmaiah3,
  3. Guillermo A. Altenberg2,
  4. Ariel F. Castro2,
  5. Glen S. Germain4,
  6. G. Krishne Gowda3 and
  7. Peter J. Houghton4
  1. 1Sealy Center for Molecular Science (J.K.H.) and2Department of Physiology and Biophysics (J.K.H., G.A.A., A.F.C.), University of Texas Medical Branch, Galveston, Texas 77555, 3Department of Studies in Chemistry, University of Mysore, Mysore-570006, India (K.N.T., G.K.G.), and 4Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38101 (G.S.G., P.J.H.)

    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

    • 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

    • ↵1 J. K. Horton, unpublished observations.

    • 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.).

    • Abbreviations:
      MDR
      multidrug resistant/resistance
      PBA
      1,3-bis(9-oxoacridin-10-yl)-propane
      VLB
      vinblastine
      VRP
      verapamil
      CsA
      cyclosporin A
      R123
      rhodamine 123
      P-gp
      P-glycoprotein
      DTT
      dithiothreitol
      HEPES
      4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
      HR
      HEPES-Ringer
      • Received July 8, 1997.
      • Accepted August 12, 1997.
    « Previous | Next Article »Table of Contents

    This Article

    1. Molecular Pharmacology December 1, 1997 vol. 52 no. 6 948-957
    1. » Abstract
    2. Full Text
    3. Full Text (PDF)

    Classifications

    Responses

    1. Submit a response
    2. No responses published

    Current Issue

    1. November 2009, 76 (5)
    1. Current Issue
    1. Alert me to new issues of Molecular Pharmacology