Differential sensitivities of MRP1-overexpressing lung tumor cells to cytotoxic metals

The human multidrug-resistance protein (MRP1), known to mediate cellular ef flux of a wide range of xenobiotics, including anticancer drugs, has also b een shown to transport antimony, thereby conferring resistance to this heav y metal. The aim of the present study was to investigate whether other cyto toxic metals could be handled by MRP1 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 te sted such as copper, chromium, cobalt or aluminium. MK571, a potent inhibit or of MRP1 activity, almost totally reversed resistance of GLC4/Sb30 cells to mercuric ions and arsenic while it did not significantly after sensitivi ty of GLC4 cells to metals. Arsenate-treated GLC4/Sb30 cells were found to poorly accumulate arsenic through increased MK571-inhibitable eff-lux of th e metal. Arsenate, however, failed to alter MRP1-mediated transport of know n MRP1 substrates such as calcein and vincristine. In conclusion, these fin dings demonstrated that MRP1 likely handled some, but not all, cytotoxic me tals such as arsenic and mercuric ions in addition to antimony, therefore r esulting in reduced toxicity of these compounds towards MRP1-overexpressing cells. (C) 2000 Published by Elsevier Science Ireland Ltd. All rights rese rved.