Contribution of tumor endothelial cells to drug resistance: anti-angiogenic tyrosine kinase inhibitors act as p-glycoprotein antagonists

• Published in: Angiogenesis (London) 2017-05, Vol.20 (2), p.233-241
• Main Authors: Bani, MariaRosa, Decio, Alessandra, Giavazzi, Raffaella, Ghilardi, Carmen
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adenocarcinoma; Adenosine triphosphatase; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Antagonists; Antiangiogenics; ATP Binding Cassette Transporter, Sub-Family B - antagonists & inhibitors; ATP Binding Cassette Transporter, Sub-Family B - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cardiology; Cell Biology; Chemoresistance; Chemotherapy; Cytotoxicity; Doxorubicin; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drugs; Endothelial cells; Gene expression; Glycoproteins; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - pathology; Humans; In vitro methods and tests; Inhibitors; Kinases; Mice; Mice, Nude; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - metabolism; Oncology; Ophthalmology; Original Paper; P-Glycoprotein; Paclitaxel; Protein Kinase Inhibitors - pharmacology; Substrates; Tyrosine; Tyrosine kinase inhibitors; Verapamil; Xenograft Model Antitumor Assays
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-017-9549-6

Tumor endothelial cells (TEC) differ from the normal counterpart, in both gene expression and functionality. TEC may acquire drug resistance, a characteristic that is maintained in vitro. There is evidence that TEC are more resistant to chemotherapeutic drugs, substrates of ATP-binding cassette (ABC) transporters. TEC express p-glycoprotein (encoded by ABCB1), while no difference in other ABC transporters was revealed compared to normal endothelia. A class of tyrosine kinase inhibitors (TKI), used as angiostatic compounds, interferes with the ATPase activity of p-glycoprotein, thus impairing its functionality. The exposure of ovarian adenocarcinoma TEC to the TKIs sunitinib or sorafenib was found to abrogate resistance (proliferation and motility) to doxorubicin and paclitaxel in vitro, increasing intracellular drug accumulation. A similar effect has been reported by the p-glycoprotein inhibitor verapamil. No beneficial effect was observed in combination with cytotoxic drugs that are not p-glycoprotein substrates. The current paper reviews the mechanisms of TEC chemoresistance and shows the role of p-glycoprotein in mediating such resistance. Inhibition of p-glycoprotein by anti-angiogenic TKI might contribute to the beneficial effect of these small molecules, when combined with chemotherapy, in counteracting acquired drug resistance.