Faculty Articles

Title

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

ISBN or ISSN

1791-2431

Publication Title

Oncology Reports

Volume

39

Issue

4

Publication Date / Copyright Date

4-2018

First Page

1711

Last Page

1724

Publisher

Spandidos Publications

DOI Number

10.3892/or.2018.6256

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.

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

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

Peer Reviewed

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