Realgar transforming solution suppresses angiogenesis and tumor growth by inhibiting VEGF receptor 2 signaling in vein endothelial cells

• DOI: 10.1007/s12272-018-1014-6
• Publication Date: 2018-03-14T23:30:04Z
• Authors: Peng Song; Yang Hai; Xin Wang; Longhe Zhao; Baoqiang Chen; Peng Cui; Qinjian Xie; Lan Yu; Yang Li; Zhengrong Wu; Hongyu Li
• Keywords: 0301 basic medicine; Dose-Response Relationship, Drug; Neovascularization, Pathologic; Carcinogenesis; Angiogenesis Inhibitors; Sulfides; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays; Arsenicals; Tumor Burden; 3. Good health; Mice; 03 medical and health sciences; Cell Line, Tumor; Human Umbilical Vein Endothelial Cells; Animals; Humans; Female; Zebrafish; Signal Transduction

Realgar (As4S4), as an arsenic sulfide mineral drug, has a good therapeutic reputation for anticancer in Traditional Chinese Medicine, and has recently been reported to inhibit angiogenesis in tumor growth. However, considering the poor solubility and low bioavailability of realgar, large dose of realgar and long period of treatment are necessary for achieving the effective blood medicine concentration. In present study, we resolved the crucial problem of poor solubility of realgar by using intrinsic biotransformation in microorganism, and investigated underlying mechanisms of realgar transforming solution (RTS) for antiangiogenesis. Our results demonstrated that RTS had a strong activity to inhibit HUVECs proliferation, migration, invasion, and tube formation. Moreover, RTS inhibited VEGF/bFGF-induced phosphorylation of VEGFR2 and the downstream protein kinases including ERK, FAK, and Src. In vivo zebrafish and chicken chorioallantoic membrane model experiments showed that RTS remarkably blocked angiogenesis. Finally, compared with the control, administration of 2.50 mg/kg RTS reached more than 50% inhibition against H22 tumor allografts in KM mice, but caused few toxic effects in the host. The antiangiogenic effect was indicated by CD31 immunohistochemical staining and alginate-encapsulated tumor cell assay. In summary, our findings suggest that RTS inhibits angiogenesis and may be a potential drug candidate in anticancer therapy.