Faculty Articles

Anti-Angiogenic and Pro-Apoptotic Effects Of a Small-Molecule JFD-WS in In Vitro and Breast Cancer Xenograft Mouse Models

Publication Title

Oncology Reports

Publisher

Spandidos Publications

ISSN

1791-2431

Publication Date

4-2018

Keywords

angiogenesis inhibitors, animals, breast neoplasms, cell line, tumor, cell proliferation, collagen, drug combinations, gene expression regulation, neoplastic, human umbilical vein endothelial cells, humans, laminin, mice, mucin-1, neovascularization, pathologic, proteoglycans, small molecule libraries, vascular endothelial growth factor receptor-2

Abstract

A small molecule that was developed for blocking vascular endothelial growth factor receptor 2 (VEGFR2) has been tested and confirmed for its anti-angiogenic activity. Subsequently, it was modified into a water soluble salt form (JFD-WS) to increase bioavailability and distribution during in vivo pre-clinical testing. The present study was designed to further evaluate the anti-angiogenic and pro-apoptotic effects of JFD-WS in monotherapy as well as in combination with paclitaxel (Taxol) using a mouse xenograft model. The in vitro anti-angiogenic effects of JFD-WS were investigated using cell proliferation, migration, Matrigel tube formation and VEGFR2 phosphorylation assays. The anti-angiogenic effect of JFD-WS was further established using chorioallantoic membrane (CAM) assay followed by in vivo efficacy testing on GI-101A breast adenocarcinoma cells. Pharmacokinetic and toxicity studies were performed using BALB/c mice. Finally, the apoptotic signals were assessed in the control and experimental tumor samples, and the plasma mucin 1 (MUC1) levels were analyzed. In the in vitro tests, JFD-WS effectively inhibited HUVEC proliferation, migration, tube formation and VEGFR2 phosphorylation. Additionally, JFD-WS inhibited the formation of blood vessels in chick chorioallantoic membrane. While inhibiting the xenograft tumor growth in experimental mice, JFD-WS decreased the plasma MUC1 levels. The western blot analysis of apoptotic markers and fragmentation analysis of DNA confirmed the pro-apoptotic effects of JFD-WS. These results indicated that JFD-WS alone or in combination with paclitaxel exerted antitumor and pro-apoptotic effects in the breast cancer xenograft model due to an anti-angiogenic effect. These results strongly support the clinical translation of its use.

DOI

10.3892/or.2018.6256

Volume

39

Issue

4

First Page

1711

Last Page

1724

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

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Peer Reviewed

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