Azithromycin effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor receptor 2‑mediated signaling pathways in lung cancer

Li,Fajiu; Huang,Jie; Ji,Dongyuan; Meng,Qinghua; Wang,Chuanhai; Chen,Shi; Wang,Xiaojiang; Zhu,Zhiyang; Jiang,Cheng; Shi,Yi; Liu,Shuang; Li,Chenghong

doi:10.3892/ol.2017.6103

Azithromycin effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor receptor 2‑mediated signaling pathways in lung cancer

Authors:
- Fajiu Li
- Jie Huang
- Dongyuan Ji
- Qinghua Meng
- Chuanhai Wang
- Shi Chen
- Xiaojiang Wang
- Zhiyang Zhu
- Cheng Jiang
- Yi Shi
- Shuang Liu
- Chenghong Li
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Affiliations: Department of Respiratory Medicine, Wuhan No. 6 Hospital, Affiliated Hospital to Jianghan University, Wuhan, Hubei 430072, P.R. China
Published online on: April 28, 2017 https://doi.org/10.3892/ol.2017.6103
Pages: 89-96
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tumor angiogenesis is essential during lung cancer development and targeting angiogenesis may possess a potential therapeutic value. The present study demonstrates that azithromycin, a Food and Drug Administration‑approved antibiotic drug, is a novel tumor angiogenesis inhibitor. Azithromycin inhibits capillary network formation of human lung tumor associated‑endothelial cells (HLT‑ECs) in vitro and in vivo. It significantly inhibits HLT‑EC adhesion and vascular endothelial growth factor (VEGF)‑induced proliferation of HLT‑ECs in a dose‑dependent manner without affecting migration. In addition, azithromycin induces apoptosis of HLT‑ECs even in the presence of VEGF. Notably, azithromycin inhibits proliferation and induces apoptosis in multiple lung cancer cell lines to a significantly reduced extent compared with in HLT‑ECs, suggesting that HLT‑ECs are more susceptible to azithromycin treatment. In a lung tumor xenograft model, azithromycin significantly inhibits tumor growth and its anti‑tumor activities are achieved by suppressing angiogenesis. Notably, the inhibitory effects of azithromycin on angiogenesis are associated with its ability to suppress VEGF‑induced activation of VEGF receptor 2 (VEGFR2), phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt), focal adhesion kinase, and disruption of focal adhesion assembly and actin stress fiber formation in HLT‑ECs. The present study identifies that azithromycin targets VEGFR2‑mediated focal adhesion and PI3K/Akt signaling pathways in HLT‑ECs, leading to the suppression of angiogenesis and lung tumor growth.

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