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Vandetanib (ZD6474) induces antiangiogenesis through mTOR–HIF-1 alpha–VEGF signaling axis in breast cancer cells

Authors Li L, Yu J, Jiao S, Wang W, Zhang F, Sun S

Received 28 May 2018

Accepted for publication 21 October 2018

Published 29 November 2018 Volume 2018:11 Pages 8543—8553

DOI https://doi.org/10.2147/OTT.S175578

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 5

Editor who approved publication: Professor Jianmin Xu


Ling Li,1,* Jingkui Yu,2,* Shuhong Jiao,1 Wei Wang,1 Fen Zhang,1 Shiqing Sun1

1Department of Oncology, Affiliated Tengzhou Central People’s Hospital of Jining Medical University, Zaozhuang, Shandong, China; 2Breast Surgery Department, Affiliated Tengzhou Central People’s Hospital of Jining Medical University, Zaozhuang, Shandong, China

*These authors contributed equally to this work

Objective: Vandetanib, also known as ZD6474, has recently been proved to be a clinical drug for cancer by targeting vascular endothelial growth factor receptor 2 (VEGFR2), EGFR, and RET tyrosine kinases. We hypothesized that vandetanib will be a drug candidate for breast cancer treatment by targeting angiogenesis.
Materials and methods: Vandetanib was used to treat different breast cancer cell lines, and its effect on growth, apoptosis, and cell cycle was studied by MTT assay and flow cytometry. VEGF level in culture medium was measured by ELISA. Gene expression of mechanistic target of rapamycin (mTOR), hypoxia-inducible factor (HIF)-1 alpha, and VEGF at mRNA and protein level were analyzed by quantitative real-time-PCR and Western blot. The cellular behavior variations were investigated by using wound healing assay, transwell invasion assay, and tubular formation assay as well as experiments in vivo.
Result: We found that vandetanib can inhibit breast cancer cell line growth via apoptosis and cell cycle regulation. VEGF secretion decreases upon treatment. Vandetanib can reduce both mRNA and protein level of mTOR, HIF-1 alpha, and VEGF. Angiogenesis assays showed that vandetanib can inhibit wound healing, invasion, and tubular formation in culture. Furthermore, vandetanib inhibited the growth of breast tumor in vivo.
Conclusion: In short, our study showed that vandetanib can control angiogenesis of breast cancer in culture via mTOR, HIF-1 alpha, and VEGF signaling pathway.

Keywords: vandetanib, HIF-1 alpha, mTOR, VEGF, breast cancer
 

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