Nakagawa Kazuhiko

Induction of MRP5 and SMRP mRNA by adriamycin exposure and its overexpression in human lung cancer cells resistant to adriamycin

Acquired anticancer drug resistance in cancer cells is often a result of an increase in levels of the ATP binding cassette (ABC) transporters that export anticancer drugs from cancer cells, suggesting that anticancer drugs may induce genes that mediate drug resistance in cancer cells. In this study, the induction of anticancer drug transporter gene expression by Adriamycin was examined in human lung cancer cell lines. Increased expression of MDR1, MRP5 and SMRP mRNA was observed 48 hr after the initiation of Adriamycin exposure in human lung cancer PC‐14 cells and cisplatin‐resistant PC‐14/CDDP cells, in a dose‐dependent manner as measured by TaqMan real‐time RT‐PCR. The levels of MRP‐1, MRP2 and LRP mRNA were not altered by Adriamycin exposure. The biologic functions of the MRP5 and SMRP genes have not been fully clarified. To elucidate the relationship between Adriamycin resistance and MRP5 and SMRP, mRNA levels of MRP5 and SMRP in Adriamycin‐resistant cell lines were compared with the parental cells. Increased expression of MRP5 and SMRP mRNA was observed in all 3 cell lines (SBC‐3/ADM, AdR MCF7 and K562/ADM) by Northern blot analysis and RNase protection assay. These results suggest that subacute exposure of lung cancer cells to Adriamycin induced MRP5 and SMRP and that long‐term exposure with Adriamycin selected the MRP5‐ and SMRP‐overexpressing lung cancer cells. MRP5 and SMRP is a candidate molecule for acquired Adriamycin resistance in addition to MDR1.