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ZD6474 Attenuates Fibrosis and Inhibits Neovascularization in Human Pterygium by Suppressing AKT-mTOR Signaling Pathway

Purpose: To investigate the antifibrotic effect of ZD6474 in human pterygium fibroblasts (HPFs) and angiogenesis in human umbilical vein endothelial cells (HUVECs) compared with mitomycin C (MMC). Methods: Pterygium and tenon fibroblasts were isolated from patients undergoing surgery to culture HPFs and human tenon fibroblasts (HTFs). The effects of ZD6474 on HPF, HTF, and HUVEC proliferation and migration were detected using CCK8 and wound-healing assays, respectively. Fibrosis and epithelial-mesenchymal transformation (EMT) were evaluated by western blotting [transforming growth factor beta (TGF-β)1/2 and snail] and immunofluorescence (vimentin and α-smooth muscle actin). The antiangiogenic effect of ZD6474 on HUVECs was assessed using a tube formation assay. To determine the potential mechanism, the expression of phosphorylated AKT (p-AKT) and phosphorylated mTOR (p-mTOR) was evaluated by treatment with ZD6474 via western blotting. Results: ZD6474 robustly inhibited the proliferation and migration of HPFs rather than HTFs compared with those in the MMC group (**P < 0.01). In HPFs, fibrosis and EMT (vimentin, TGF-β1/2, and snail) were significantly reversed by ZD6474. MMC (>50 μg/mL) significantly reduced HTF viability, whereas ZD6474 (<5 μM/mL) did not decrease HTF viability. HUVEC proliferation and migration were clearly decreased, and tube formation was notably interrupted by ZD6474. Activation of p-AKT and p-mTOR was inhibited by ZD6474 treatment of HPFs and HUVECs. Conclusion: ZD6474 is more effective than MMC in reducing fibrosis and EMT in HPFs. In addition, ZD6474 was less toxic to HTFs. ZD6474 also exhibited antiangiogenic effects in HUVECs. This study may aid in the development of novel agents to prevent pterygium recurrence after pterygium excision.

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S1046 Vandetanib Vandetanib is a potent inhibitor of VEGFR2 with IC50 of 40 nM in a cell-free assay. It also inhibits VEGFR3 and EGFR with IC50 of 110 nM and 500 nM, respectively. Not sensitive to PDGFRβ, Flt1, Tie-2 and FGFR1 with IC50 of 1.1-3.6 μM. No activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt and IGF-1R with IC50 above 10 μM. Vandetanib (ZD6474) increases apoptosis and induces autophagy by increasing the level of reactive oxygen species (ROS).

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Apoptosis related EGFR VEGFR Autophagy ROS