Reversal of MRP-mediated multidrug resistance in human lung cancer cells by the antiprogestatin drug RU486.
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Payen L, Delugin L, Courtois A, Trinquart Y, Guillouzo A, Fardel O
Reversal of MRP-mediated multidrug resistance in human lung cancer cells by the antiprogestatin drug RU486.
Biochem Biophys Res Commun. 1999 May 19;258(3):513-8.
- PubMed ID
- 10329417 [ View in PubMed]
- Abstract
Multidrug resistance-associated protein (MRP) and P-glycoprotein (P-gp) are drug efflux pumps conferring multidrug resistance to tumor cells. RU486, an antiprogestatin drug known to inhibit P-gp function, was examined for its effect on MRP activity in MRP-overexpressing lung tumor GLC4/Sb30 cells. In such cells, the antihormone compound was found to increase intracellular accumulation of calcein, a fluorescent compound transported by MRP, in a dose-dependent manner, through inhibition of cellular export of the dye; in contrast, it did not alter calcein levels in parental GLC4 cells. RU486, when used at 10 microM, a concentration close to plasma concentrations achievable in humans, strongly enhanced the sensitivity of GLC4/Sb30 cells towards two known cytotoxic substrates of MRP, the anticancer drug vincristine and the heavy metal salt potassium antimonyl tartrate. Vincristine accumulation levels were moreover up-regulated in RU486-treated GLC4/Sb30 cells. In addition, such cells were demonstrated to display reduced cellular levels of glutathione which is required for MRP-mediated transport of some anticancer drugs. These findings therefore demonstrate that RU486 can down-modulate MRP-mediated drug resistance, in addition to that linked to P-gp, through inhibition of MRP function.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Mifepristone Multidrug resistance-associated protein 1 Protein Humans UnknownInhibitorDetails Probenecid Multidrug resistance-associated protein 1 Protein Humans UnknownInhibitorDetails Progesterone Multidrug resistance-associated protein 1 Protein Humans UnknownInhibitorDetails