Blockade of vascular endothelial growth factor receptors by tivozanib has potential anti-tumour effects on human glioblastoma cells

Abstract

Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.

Effect of Foretinib on Matrix Metalloproteinase-2 (MMP2) Expression in Glioblastoma

“…GBM invasion. [19][20][21] In conclusion, our data demonstrated that treatment with foretinib leads to downregulation of MMP2 in GBM cell line and has a positive effect on T98 cells…”

Cytocidal effects of arenobufagin and hellebrigenin, two active bufadienolide compounds, against human glioblastoma cell line U-87

“…Concomitantly, a remarkable downregulation of the expression levels of Cdc25C and Cyclin B1, key regulators involved in the G 2 /M cell cycle transition ( 37 , 38 ), was further observed in the treated cells compared with the control (untreated cells). A number of previous studies have demonstrated that in glioblastoma cell lines, downregulation of the expression levels of Cdc25C and Cyclin B1 has been implicated in the G 2 /M phase arrest induced by various antitumor agents, including arsenic trioxide ( 39 ), tivozanib, a pan-inhibitor of vascular endothelial growth factor ( 40 ), and knockdown of β-arrestin 1, a mediator of tachykinin receptor neurokinin-1 signaling pathway responsible for cell proliferation ( 41 ). Survivin, an important cancer-associated protein, is highly expressed in the majority of human tumor cells, including primary human glioblastoma cells ( 19 ), and its inhibition has been considered as a compelling strategy for cancer therapy ( 42 ).…”

Dacomitinib, a pan-inhibitor of ErbB receptors, suppresses growth and invasive capacity of chemoresistant ovarian carcinoma cells

“…The target gene expression levels were normalised to beta-2-microglobulin ( B2M ) levels in the same reaction. For calculations, 2 −ΔΔC T formula was used, with ΔΔC T  = (C T target − C T B2M ) experimental sample – (C T target − C T B2M ) control samples, where C T is cycle threshold 79 .…”