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.

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

“…One might hypothesize that ET A R-mediated ABCB1 activation is a consequence of the specific nintedanib target profile including major players in endothelial cell physiology like FGFR and VEGFR. Indeed, in a study by Huang et al, selection against the VEGFR/PDGFR angiokinase inhibitor sunitinib led to induction of ABCB1 expression in transformed HMEC-1 endothelial cells [43]. Alternatively, based on the dominance of gene amplification and epigenetic regulation in ABCB1-mediated MDR, the impact of such more subtle physiological mechanisms might have been overlooked so far in the malignant background.…”

A New Antitumor Direction: Tumor-Specific Endothelial Cells

“…However, it is not clear whether this resistance is related to the genomic characteristics of TECs. The resistance of ECs to antiangiogenic treatment appears to be related to the increased expression of multidrug resistance proteins, such as Pglycoprotein (Pgp, ABCB1) and breast cancer resistance protein (BCRP,ABCG2), which serve as cellular efflux pumps (101,102). In addition, Ca2+ transporters are also changed in stromal cancer cells, including ECs and endothelial colony forming cells (103).…”

The Challenges of Modeling Drug Resistance to Antiangiogenic Therapy

“…For example, Huang et al [27] and Guerrouahen et al [28] show that chronic exposure of sunitinib or bevacizumab in vitro to (non-transformed) vascular endothelial cells can lead to upregulation of multidrug resistant proteins (such as P-glycoprotein) or compensatory angiogenic signals (such as FGF), respectively. This lack of in vitro study may be due, at least in part, to the technical difficulty of establishing resistance in ‘normal’ VEGFR2 + endothelial cells as limited passages and need for growth factor stimulation ( i.e.…”