Characterization of a novel bisacridone and comparison with PSC 833 as a potent and poorly reversible modulator of P-glycoprotein.
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 microM, increased steady state accumulation of vinblastine (VLB) approximately 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 microM 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.
Horton
J K
JK
Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston 77555, USA. horton1@niehs.nih.gov
Thimmaiah
K N
KN
Altenberg
G A
GA
Castro
A F
AF
Germain
G S
GS
Gowda
G K
GK
Houghton
P J
PJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology*; D054831:Acridones; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D007624:KB Cells; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000493:pharmacokinetics / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D054831:Acridones; D000972:Antineoplastic Agents, Phytogenic; D003524:Cyclosporins; D005456:Fluorescent Dyes; D012235:Rhodamines; D020112:Rhodamine 123; D014747:Vinblastine; C041300:acridone; D000251:Adenosine Triphosphatases; C070272:valspodar