The antiprogestatin drug RU 486 potentiates doxorubicin cytotoxicity in multidrug resistant cells through inhibition of P-glycoprotein function.
The antiprogestatin drug RU 486 was examined for its effect on doxorubicin cellular retention and cytotoxicity in multidrug resistant cells overexpressing P-glycoprotein (P-gp). RU 486 was shown to strongly enhance intracellular accumulation of doxorubicin in both rat hepatoma RHC1 and human leukemia K562 R7 drug-resistant cells but had no action in SDVI drug-sensitive liver cells. The antiprogestatin drug when used at 10 microM, a concentration close to plasma concentrations achievable in humans, was able to hugely increase the sensitivity of RHC1 cells to doxorubicin. RU 486 appeared to prevent the P-gp-mediated doxorubicin efflux out of RHC1 cells and was demonstrated to interfere directly with P-gp drug binding sites since it blocked P-gp labelling by the photoactivable P-gp ligand azidopine. These results thus demonstrate that RU 486 can downmodulate anticancer drug resistance through inhibition of P-gp function.
Lecureur
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V
Unité de Recherches Hépatoloques U 49 de l'INSERM, Hôpital de Pontchaillou, Rennes, France.
Fardel
O
O
Guillouzo
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D002478:Cells, Cultured; D004317:Doxorubicin / Q000008:administration & dosage*; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D015735:Mifepristone / Q000008:administration & dosage*; D011374:Progesterone / Q000008:administration & dosage; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015735:Mifepristone; D011374:Progesterone; D004317:Doxorubicin; D014700:Verapamil