Lapatinib enhances the cytotoxic effects of doxorubicin in MCF-7 tumorspheres by inhibiting the drug efflux function of ABC transporters

Increasing evidences indicate that cancer stem cells are resistant to chemotherapy due to their cell quiescence and the expression of ATP-binding cassette (ABC) transporters. In this study, we utilized tumorsphere cultures to seek better strategies to overcome chemoresistance since tumorsphere cultures have been used widely for the enrichment of cancer stem cells. We found that tumorspheres generated from MCF-7 human breast cancer cells exhibited high proportions of quiescent cells and expressed MDR-1 at elevated levels, leading to resistance to 5-fluorouracil, paclitaxel, and doxorubicin. Because the expression of EGFR/HER2 was increased in MCF-7 tumorspheres, we assessed the combinational effect of the dual ErbB1/ErbB2 inhibitor, lapatinib, with doxorubicin in tumorspheres. The results showed that inhibition of EGFR/HER2 signaling by lapatinib sensitized MCF-7 tumorspheres to doxorubicin by inhibiting the expression of the ABC transporters, MDR-1 and BCRP, and thus, enhancing the intracellular accumulation of doxorubicin. These findings suggest that combinations of lapatinib and cytotoxic anticancer drugs may offer an advantage for treating the drug-resistant cancers. (C) 2015 Elsevier Masson SAS. All rights reserved.