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Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells

View Article: PubMed Central - PubMed

ABSTRACT

Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy. Despite initial therapeutic response, the majority of advanced-stage patients relapse and succumb to chemoresistant disease. Overcoming drug resistance is the key to successful treatment of EOC. Members of vascular endothelial growth factor (VEGF) family are overexpressed in EOC and play key roles in its malignant progression though their contribution in development of the chemoresistant disease remains elusive. Here we show that expression of the VEGF family is higher in therapy-resistant EOC cells compared to sensitive ones. Overexpression of VEGFR2 correlated with resistance to cisplatin and combination with VEGFR2-inhibitor apatinib synergistically increased cisplatin sensitivity. Tivozanib, a pan-inhibitor of VEGF receptors, reduced proliferation of the chemoresistant EOC cells through induction of G2/M cell cycle arrest and apoptotic cell death. Tivozanib decreased invasive potential of these cells, concomitant with reduction of intercellular adhesion molecule-1 (ICAM-1) and diminishing the enzymatic activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-2 (MMP-2). Moreover, tivozanib synergistically enhanced anti-tumour effects of EGFR-directed therapies including erlotinib. These findings suggest that the VEGF pathway has potential as a therapeutic target in therapy-resistant EOC and VEGFR blockade by tivozanib may yield stronger anti-tumour efficacy and circumvent resistance to EGFR-directed therapies.

No MeSH data available.


Related in: MedlinePlus

Effects of tivozanib on activation of pertinent oncogenic pathways.The cells were treated with tivozanib for 48 h then whole cell lysates were prepared and resolved by SDS PAGE. Samples were blotted for the phospho-form and re-probed for the respective total form of VEGFR2, STAT3, NF-κB p65, AKT and ERK1/2. β-actin was used as the loading control. The concentrations of tivozanib were 5, 10 and 20 μM. The blots are representative of three independent experiments with similar results.
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f5: Effects of tivozanib on activation of pertinent oncogenic pathways.The cells were treated with tivozanib for 48 h then whole cell lysates were prepared and resolved by SDS PAGE. Samples were blotted for the phospho-form and re-probed for the respective total form of VEGFR2, STAT3, NF-κB p65, AKT and ERK1/2. β-actin was used as the loading control. The concentrations of tivozanib were 5, 10 and 20 μM. The blots are representative of three independent experiments with similar results.

Mentions: The VEGF/VEGFR pathway causes a cascade of downstream events including activation of Ras/MEK/ERK axis44. In ovarian carcinoma tissues, activation of STAT3 correlates with expression of VEGFA, VEGFR1 and VEGFR245. In addition, a positive association between expression of VEGFR2 and AKT activation has been demonstrated in EOC clinical samples46. Western blot analysis was applied to explore the effects of tivozanib-mediated inhibition of p-VEGFR2 on AKT, ERK1/2, STAT3 and NF-κB pathways. Tivozanib at higher doses attenuated AKT, ERK1/2 and NF-κB pathways in OVCAR3 and A2780CP cells. In comparison, tivozanib treatment induced p-ERK1/2 in SKOV3 cells, suggesting that ERK1/2 activation might be a compensatory mechanism for inhibition of VEGFR signalling in these cells (Fig. 5).


Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells
Effects of tivozanib on activation of pertinent oncogenic pathways.The cells were treated with tivozanib for 48 h then whole cell lysates were prepared and resolved by SDS PAGE. Samples were blotted for the phospho-form and re-probed for the respective total form of VEGFR2, STAT3, NF-κB p65, AKT and ERK1/2. β-actin was used as the loading control. The concentrations of tivozanib were 5, 10 and 20 μM. The blots are representative of three independent experiments with similar results.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382685&req=5

f5: Effects of tivozanib on activation of pertinent oncogenic pathways.The cells were treated with tivozanib for 48 h then whole cell lysates were prepared and resolved by SDS PAGE. Samples were blotted for the phospho-form and re-probed for the respective total form of VEGFR2, STAT3, NF-κB p65, AKT and ERK1/2. β-actin was used as the loading control. The concentrations of tivozanib were 5, 10 and 20 μM. The blots are representative of three independent experiments with similar results.
Mentions: The VEGF/VEGFR pathway causes a cascade of downstream events including activation of Ras/MEK/ERK axis44. In ovarian carcinoma tissues, activation of STAT3 correlates with expression of VEGFA, VEGFR1 and VEGFR245. In addition, a positive association between expression of VEGFR2 and AKT activation has been demonstrated in EOC clinical samples46. Western blot analysis was applied to explore the effects of tivozanib-mediated inhibition of p-VEGFR2 on AKT, ERK1/2, STAT3 and NF-κB pathways. Tivozanib at higher doses attenuated AKT, ERK1/2 and NF-κB pathways in OVCAR3 and A2780CP cells. In comparison, tivozanib treatment induced p-ERK1/2 in SKOV3 cells, suggesting that ERK1/2 activation might be a compensatory mechanism for inhibition of VEGFR signalling in these cells (Fig. 5).

View Article: PubMed Central - PubMed

ABSTRACT

Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy. Despite initial therapeutic response, the majority of advanced-stage patients relapse and succumb to chemoresistant disease. Overcoming drug resistance is the key to successful treatment of EOC. Members of vascular endothelial growth factor (VEGF) family are overexpressed in EOC and play key roles in its malignant progression though their contribution in development of the chemoresistant disease remains elusive. Here we show that expression of the VEGF family is higher in therapy-resistant EOC cells compared to sensitive ones. Overexpression of VEGFR2 correlated with resistance to cisplatin and combination with VEGFR2-inhibitor apatinib synergistically increased cisplatin sensitivity. Tivozanib, a pan-inhibitor of VEGF receptors, reduced proliferation of the chemoresistant EOC cells through induction of G2/M cell cycle arrest and apoptotic cell death. Tivozanib decreased invasive potential of these cells, concomitant with reduction of intercellular adhesion molecule-1 (ICAM-1) and diminishing the enzymatic activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-2 (MMP-2). Moreover, tivozanib synergistically enhanced anti-tumour effects of EGFR-directed therapies including erlotinib. These findings suggest that the VEGF pathway has potential as a therapeutic target in therapy-resistant EOC and VEGFR blockade by tivozanib may yield stronger anti-tumour efficacy and circumvent resistance to EGFR-directed therapies.

No MeSH data available.


Related in: MedlinePlus