title: Induction of multiple drug resistance in HMEC-1 endothelial cells after long-term exposure to sunitinib.
abstract: Multiple drug resistance is still an unsolved problem in cancer therapy. Our previous study demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein (P-gp) in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of Dox treatment in a mice tumor model. In this study, we exposed human microvascular endothelial cells (HMEC-1) to sunitinib, a tyrosine kinase receptor inhibitor, to induce drug resistance. The results show that sunitinib treatment induced multiple drug resistance in these cells. They became resistant not only to sunitinib but also to Dox, paclitaxel, and vinblastine. Significant increases in P-gp (9.3-fold), ABCG2 (breast cancer resistance protein, 1.9-fold), and multidrug resistance-associated protein 1 (2.7-fold) gene transcription were found by quantitative polymerase chain reaction quantification, and their protein expression was confirmed by Western blot. These increases gave rise to an approximately five-fold increase in half maximal inhibitory concentration in these cells in response to sunitinib treatment in vitro. The inhibitors of adenosine triphosphate-binding cassette transporters did not reverse the drug resistance in sunitinib-resistant HMEC-1 cells, assumedly because of a blockage of the pump function caused by sunitinib. Our study indicates that the antiangiogenic drug sunitinib induces multiple drug resistance in endothelial cells. The induction of adenosine triphosphate-binding cassette transporters seems not to be responsible for observed multiple drug resistance, and the underlying mechanisms remain unknown.
authors.affiliation: Department of Oncology, People's Hospital of Guizhou Province, Guiyang, People's Republic of China.
authors.forename: Limin
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Surgery, Affiliated Hospital, Guiyang Medical University, Guiyang, People's Republic of China.
authors.forename: Chaoquan
authors.initials: C
authors.lastname: Hu
authors.affiliation: INSERM UMR-S 1165, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Di Benedetto
authors.affiliation: MERCI (EA 3829), Faculté de Médecine et de Pharmacie, Université de Rouen, Rouen, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Varin
authors.affiliation: Department of Surgery, Affiliated Hospital, Guiyang Medical University, Guiyang, People's Republic of China ; INSERM UMR-S 1165, Paris, France.
authors.forename: Jielin
authors.initials: J
authors.lastname: Liu
authors.affiliation: INSERM UMR-S 1165, Paris, France.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: MERCI (EA 3829), Faculté de Médecine et de Pharmacie, Université de Rouen, Rouen, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vannier
authors.affiliation: INSERM UMR-S 1165, Paris, France ; School of Medicine and Pharmaceutics, Jiangnan University, Wuxi, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: INSERM UMR-S 1165, Paris, France ; Université Paris Diderot, Laboratoire de Pathologie, Paris, France ; AP-HP-Hôpital Saint-Louis, Laboratoire de Pathologie, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.affiliation: INSERM UMR-S 1165, Paris, France ; Université Paris Diderot, Laboratoire de Pathologie, Paris, France.
authors.forename: He
authors.initials: H
authors.lastname: Lu
authors.affiliation: MERCI (EA 3829), Faculté de Médecine et de Pharmacie, Université de Rouen, Rouen, France.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
keywords: ABC family; cancer therapy; drug resistance; endothelial cells; sunitinib