Breast cancer resistance
protein (BCRP) is an
ATP binding cassette transporter that confers resistance to a series of
anticancer agents such as
7-ethyl-10-hydroxycamptothecin (SN-38),
topotecan, and
mitoxantrone. In this study, we evaluated the possible interaction of
gefitinib, a selective
epidermal growth factor receptor tyrosine kinase inhibitor, with BCRP. BCRP-transduced human
epidermoid carcinoma A431 (A431/BCRP) cells acquired cellular resistance to
gefitinib, suggesting that BCRP could be one of the determinants of
gefitinib sensitivity in a certain sort of cells. Next, the effect of
gefitinib on BCRP-mediated drug resistance was examined.
Gefitinib reversed
SN-38 resistance in BCRP-transduced human
myelogenous leukemia K562 (K562/BCRP) or BCRP-transduced murine
lymphocytic leukemia P388 (P388/BCRP) cells but not in these parental cells. In addition,
gefitinib sensitized human
colon cancer HT-29 cells, which endogenously express BCRP, to
SN-38.
Gefitinib increased intracellular accumulation of
topotecan in K562/BCRP cells and suppressed
ATP-dependent transport of
estrone 3-sulfate, a substrate of BCRP, in membrane vesicles from K562/BCRP cells. These results suggest that
gefitinib may overcome BCRP-mediated drug resistance by inhibiting the pump function of BCRP. Furthermore, P388/BCRP-transplanted mice treated with combination of
irinotecan and
gefitinib survived significantly longer than those treated with
irinotecan alone or
gefitinib alone. In conclusion,
gefitinib is shown to interact with BCRP. BCRP expression in a certain sort of cells is supposed to be one of the determinants of
gefitinib sensitivity.
Gefitinib inhibits the transporter function of BCRP and reverses BCRP-mediated drug resistance both in vitro and in vivo.