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

Archives of Pharmacal Research volume 41, pages 467–480 (2018)Cite this article

Abstract

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.

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Acknowledgements

This work was supported by the Sub-Project of National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2015ZX09501-004-003-008); the National Natural Science Foundation of China (grant numbers 81560715, 81403145).

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Affiliations

  1. School of Life Sciences, Institute of Microbiology, Lanzhou University, Tianshui Road No. 222, Lanzhou, 730000, China

    Peng Song, Qinjian Xie & Hongyu Li

  2. School of Pharmacy, Lanzhou University, Donggang Road No. 199, Lanzhou, 730000, China

    Yang Hai, Xin Wang, Longhe Zhao, Baoqiang Chen, Peng Cui, Lan Yu, Yang Li, Zhengrong Wu & Hongyu Li

  3. Key Laboratory of Prevention and Treatment for Chronic Disease by Traditional Chinese Medicine of Gansu Province, Jiayuguan West Road No. 732, Lanzhou, 730000, China

    Peng Song

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  1. Peng Song
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  2. Yang Hai
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  3. Xin Wang
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  4. Longhe Zhao
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  5. Baoqiang Chen
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  8. Lan Yu
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  9. Yang Li
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  10. Zhengrong Wu
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  11. Hongyu Li
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Correspondence to Hongyu Li.

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Song, P., Hai, Y., Wang, X. et al. Realgar transforming solution suppresses angiogenesis and tumor growth by inhibiting VEGF receptor 2 signaling in vein endothelial cells. Arch. Pharm. Res. 41, 467–480 (2018). https://doi.org/10.1007/s12272-018-1014-6

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  • DOI: https://doi.org/10.1007/s12272-018-1014-6

Keywords

  • Realgar transforming solution
  • Angiogenesis
  • Tumor growth
  • VEGF receptor 2
  • Vein endothelial cell