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

Huang,Limin; Hu,Chaoquan; Di Benedetto,Mélanie; Varin,Rémi; Liu,Jielin; Jin,Jian; Wang,Li; Vannier,Jean‑Pierre; Janin,Anne; Lu,He; Li,Hong

doi:10.3892/ol.2014.2819

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

Authors:
- Limin Huang
- Chaoquan Hu
- Mélanie Di Benedetto
- Rémi Varin
- Jielin Liu
- Jian Jin
- Li Wang
- Jean‑Pierre Vannier
- Anne Janin
- He Lu
- Hong Li
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Affiliations: Department of Oncology, People's Hospital of Guizhou Province, Guiyang, Guizhou 550000, P.R. China, Department of Surgery, Affiliated Hospital of Guiyang Medical University, Guiyang, Guizhou 550004, P.R. China, French Institute of Health and Medical Research, UMR‑S 1165, University Institute of Hematology, Saint Louis Hospital, Paris 75010, France, Laboratory of MERCI (EA 3829), Faculty of Medicine and Pharmacy, University of Rouen, Rouen 76183, France
Published online on: December 22, 2014 https://doi.org/10.3892/ol.2014.2819
Pages: 1287-1292

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Abstract

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 in vitro. 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.

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