Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells.

Multiple drug resistance remains an unsolved problem in cancer therapy. A previous study has demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of doxorubicin treatment in a mouse tumor model. In the present study, the cross-resistance and sensitivity of HMECd1 and HMECd2 established cell lines to anti-angiogenic drugs, particularly sunitinib, was explored. The results revealed that Dox treatment induced a significant increase in the breast cancer resistance protein (ABCG2) gene transcription and protein expression. This increase gave rise to a 4- to 5-fold increase in the half maximal inhibitory concentration of the HMECd1 and HMECd2 cells in response to sunitinib treatment . Functionally, the role of ABCG2 in the resistance to sunitinib was confirmed by the use of the ABCG2 inhibitors fumitremorgin C and diethylstilbestrol, which blocked cell resistance. The present study indicates that endothelial cells exhibit cross-resistance between cytotoxic drugs and anti-angiogenic drugs. This suggests that multiple drug resistance induced by chemotherapy in endothelial cells may affect the efficiency of anti-angiogenic drugs.