Hypoxia-induced acidification causes mitoxantrone resistance not mediated by drug transporters in human breast cancer cells.

Hypoxia has clinically been associated with resistance to chemotherapy. The aim of this study was to investigate whether hypoxia induces resistance to doxorubicin and mitoxantrone, two common drugs in cancer treatment, in MCF-7 breast cancer cells, and SW1573 non-small lung cancer cells. In addition, the role of drug transporters P-gp, BCRP and MRP1 was analysed. Hypoxia induced resistance in MCF-7 cells to mitoxantrone shifted the IC(50) value from 0.09 microM (+/-0.01) to 0.54 microM (+/-0.06) under hypoxia, whereas survival of MCF-7 and SW1573 cells in the presence of doxorubicin was not altered. Accumulation of mitoxantrone and daunorubicin, a doxorubicin fluorescent homologue, appeared to be 5.3 and 3.2 times lower in MCF-7 cells, respectively. Cytotoxicity assays showed no increased functionality of the drug transporters P-gp, BCRP and MRP1 under hypoxia. In addition, protein levels of these drug transporters were not changed. Medium of the MCF-7 cells became more acidic under hypoxia thereby causing a decreased uptake of mitoxantrone. Hypoxia induces mitoxantrone resistance in MCF-7 cells not mediated by the three major MDR transporters. Hypoxia-induced acidification may cause this resistance by decreased cellular uptake together with a lowered cytotoxicity due to pH-dependent topoisomerase type II activity.