Antitumor effect of FP3 in a breast cancer xenograft model

Abstract

FP3 is a novel vascular endothelial growth factor (VEGF) blocker proposed to have antiangiogenic properties. Previous studies revealed that FP3 is a new promising agent for treating human choroidal neovascularization (CNV)-associated age-associated macular degeneration (AMD) and has an inhibitory effect on VEGF-mediated proliferation and migration of human umbilical vein endothelial cells and VEGF-mediated vessel sprouting of the rat aortic ring in vitro. Previous studies have also revealed that FP3 has antitumor effects and antiangiogenic effects in a non-small cell lung cancer cell line (A549), as well as in patient-derived tumor tissue xenograft models of gastric cancer and colon carcinoma with lymphatic and hepatic metastases in nude mice. In the present study, the antitumor effect of FP3 in an MDA-MB-231 breast cancer xenograft model was investigated. Treatment with FP3 for 3 weeks significantly suppressed xenograft growth and this inhibition was associated with a significant decrease in angiogenesis and direct inhibition of tumor cells. The results of the present study indicate that FP3 inhibits breast cancer tumor growth via the indirect inhibition of angiogenesis as well as a direct effect on tumor cells.

Figure 1

Antiproliferative effect of FP3 on MDA-MB-231 cells in vitro. Clonogenicity of MDA-MB-231 cells was reduced by 77, 82, and 89% following treatment with 20, 50 amd 100 μg/ml FP3, respectively, for 10 days at 37°C. Cell proliferation was normalized to NS controls. Data are the mean ± SEM from 3 independent experiments. ^* p<0.01, vs. NS control. NS, normal saline.

Figure 2

FP3 significantly inhibits the subcutaneous growth of implanted MDA-MB-231 tumors. FP3 substantially blocked the growth of the subcutaneously implanted tumor when administered at the indicated doses twice weekly for 3 weeks. Error bars represent the standard error of mean; n=8 mice/treatment group. Data shown are the mean ± SEM. The differences between control tumor volumes, Avastin-treated and FP3-treated tumor volumes were analyzed using one-way ANOVA. ^*p<0.001, vs. NS control. NS, normal saline.

Figure 3

FP3 decreased vascular structure. Vasculature was examined by angiography with immunostaining for endothelial cells (using anti-PECAM-1 antibody; bar=100 μm). NS, normal saline; PECAM-1, platelet endothelial cell adhesion molecule-1.