E7050 Suppresses the Growth of Multidrug-Resistant Human Uterine Sarcoma by Inhibiting Angiogenesis via Targeting of VEGFR2-Mediated Signaling Pathways

by Selleckchem | Dec 24 2023

E7050 is an inhibitor of VEGFR2 with anti-tumor activity; however, its therapeutic mechanism remains incompletely understood. In the present study, we aim to evaluate the anti-angiogenic activity of E7050 in vitro and in vivo and define the underlying molecular mechanism. It was observed that treatment with E7050 markedly inhibited proliferation, migration, and capillary-like tube formation in cultured human umbilical vein endothelial cells (HUVECs). E7050 exposure in the chick embryo chorioallantoic membrane (CAM) also reduced the amount of neovessel formation in chick embryos. To understand the molecular basis, E7050 was found to suppress the phosphorylation of VEGFR2 and its downstream signaling pathway components, including PLCγ1, FAK, Src, Akt, JNK, and p38 MAPK in VEGF-stimulated HUVECs. Moreover, E7050 suppressed the phosphorylation of VEGFR2, FAK, Src, Akt, JNK, and p38 MAPK in HUVECs exposed to MES-SA/Dx5 cells-derived conditioned medium (CM). The multidrug-resistant human uterine sarcoma xenograft study revealed that E7050 significantly attenuated the growth of MES-SA/Dx5 tumor xenografts, which was associated with inhibition of tumor angiogenesis. E7050 treatment also decreased the expression of CD31 and p-VEGFR2 in MES-SA/Dx5 tumor tissue sections in comparison with the vehicle control. Collectively, E7050 may serve as a potential agent for the treatment of cancer and angiogenesis-related disorders.

Comments:

The study you provided demonstrates the potential of E7050 as an inhibitor of VEGFR2 with significant anti-tumor and anti-angiogenic activity. Here's a breakdown of the findings and their implications:

1. **In Vitro Effects:** E7050 showed inhibitory effects on various aspects of endothelial cell function, including proliferation, migration, and tube formation, which are critical for angiogenesis—the formation of new blood vessels.

2. **In Vivo Effects:** The study extended its analysis to chick embryos' chorioallantoic membrane (CAM), a model system for studying angiogenesis. E7050 reduced neovessel formation, further supporting its anti-angiogenic potential.

3. **Molecular Mechanisms:** E7050's action involves the suppression of VEGFR2 phosphorylation and downstream signaling molecules (PLCγ1, FAK, Src, Akt, JNK, and p38 MAPK) in response to VEGF stimulation in endothelial cells. Additionally, it showed similar effects in cells exposed to conditioned medium from tumor cells, indicating its efficacy under tumor microenvironment conditions.

4. **In Vivo Xenograft Study:** The anti-tumor effect was confirmed in a xenograft model using multidrug-resistant human uterine sarcoma cells (MES-SA/Dx5). E7050 treatment reduced tumor growth and angiogenesis. Reduced expression of CD31 (a marker for blood vessels) and phosphorylated VEGFR2 in tumor tissue further supported its anti-angiogenic effects.

The study's findings suggest that E7050 could be a promising therapeutic agent for cancer treatment by targeting both tumor growth and the formation of new blood vessels crucial for tumor progression. Its ability to inhibit VEGFR2 and downstream signaling pathways in endothelial cells and the tumor microenvironment underscores its potential in controlling angiogenesis-related disorders.