Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models

Rathinavelu,Appu; Kanagasabai,Thanigaivelan; Dhandayuthapani  ,Sivanesan; Alhazzani,Khalid

doi:10.3892/or.2018.6256

Anti-angiogenic and pro-apoptotic effects of a small-molecule JFD-WS in in vitro and breast cancer xenograft mouse models

Authors:
- Appu Rathinavelu
- Thanigaivelan Kanagasabai
- Sivanesan Dhandayuthapani
- Khalid Alhazzani
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Affiliations: Rumbaugh-Goodwin Institute for Cancer Research, College of Pharmacy, Health Professions Division, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
Published online on: February 9, 2018 https://doi.org/10.3892/or.2018.6256
Pages: 1711-1724

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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.

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