Differential sensitivities of MRP1-overexpressing lung tumor cells to cytotoxic metals.
The human multidrug-resistance protein (MRP1), known to mediate cellular efflux of a wide range of xenobiotics, including anticancer drugs, has also been shown to transport antimony, thereby conferring resistance to this heavy metal. The aim of the present study was to investigate whether other cytotoxic metals could be handled by MRPI using MRP1-overexpressing lung tumor GLC4/Sb30 cells. Such cells were found to be 3.4-, 12.7- and 16.3-fold more resistant than parental GLC4 cells to mercuric ion, arsenite and arsenate, respectively, whereas they remained sensitive to other cytotoxic metals tested such as copper, chromium, cobalt or aluminium. MK571, a potent inhibitor of MRP1 activity, almost totally reversed resistance of GLC4/Sb30 cells to mercuric ions and arsenic while it did not significantly alter sensitivity of GLC4 cells to metals. Arsenate-treated GLC4/Sb30 cells were found to poorly accumulate arsenic through increased MK571-inhibitable efflux of the metal. Arsenate, however, failed to alter MRP1-mediated transport of known MRP1 substrates such as calcein and vincristine. In conclusion, these findings demonstrated that MRP1 likely handled some, but not all, cytotoxic metals such as arsenic and mercuric ions in addition to antimony, therefore resulting in reduced toxicity of these compounds towards MRP1-overexpressing cells.
Vernhet
L
L
INSERM U456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, France. laurent.vernhet@rennes.inserm.fr
Allain
N
N
Bardiau
C
C
Anger
J P
JP
Fardel
O
O
D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000502:physiology*; D000965:Antimony / Q000378:metabolism / Q000633:toxicity; D001151:Arsenic / Q000378:metabolism / Q000633:toxicity; D018432:Drug Resistance, Multiple; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008628:Mercury / Q000378:metabolism / Q000633:toxicity; D008670:Metals / Q000633:toxicity*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000965:Antimony; D001151:Arsenic; D008628:Mercury; D008670:Metals; D027425:ATP-Binding Cassette, Sub-Family C Proteins