Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a

Summary

The pharmacokinetic (PK) and potential effects of Emodin on liver cancer were systematically evaluated in this study. Both the intragastric administration (i.g.) and hypodermic injection (i.h.) of Emodin exhibited a strong absorption (absorption rate < 1 h) and elimination capacity (t1/2 ≈ 2 h). The tissue distribution of Emodin after i.h. was rapid and wide. The stability of Emodin in three species of liver microsomes wasrat >human> beagle dog. These PK data provided the basis for the subsequent animal experiments. In liver cancer patient tissues, the expression of vascular endothelial growth factor (VEGF)-induced signaling pathways, including phosphorylated VEGF receptor 2 (VEGFR2), AKT, and ERK1/2,were simultaneously elevated, but miR-34a expression was reduced and negatively correlated with SMAD2 and SMAD4. Emodin inhibited the expression of SMAD2/4 in HepG2 cells by inducing the miR-34a level. Subsequently, BALB/c nude mice received a daily subcutaneous injection of HepG2 cells with or without Emodin treatment (1 mg/kg or 10 mg/kg), and Emodin inhibited tumorigenesis and reduced the mortality rate in a dose-dependent manner. In vivo experiments showed that cell proliferation, migration, and invasion were promoted by VEGF or miR-34a signal treatment but were inhibited when combined with Emodin treatment. All these results demonstrated that Emodin inhibited tumorigenesis in liver cancer by simultaneously inhibiting the VEGFR2-AKT-ERK1/2signaling pathway and promoting a miR-34a-mediated signaling pathway.

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Funding

This work was supported by funding from the Fourth Hospital of Hebei Medical University.

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Contributions

R.T. and J. B. designed the experiments; C.S. performed the animal experiments; J. J. performed the cell experiments in vitro; Z. Y. and W. Y. performed the western blot analysis and the luciferase assay; G. M. and J. W. performed the immunohistochemistry assay; and J. B. analyzed the data and drafted the manuscript.

Corresponding author

Correspondence to Ruifeng Tang.

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Conflict of interest

All authors have declared that they have no conflicts of interest to disclose. Jianguo Bai declares that he has no conflict of interest. Jianfei Wu declares that he has no conflict of interest. Ruifeng Tang declares that he has no conflict of interest. Chao Sun declares that he has no conflict of interest. Junwei Ji declares that he has no conflict of interest. Zhaolin Yin declares that he has no conflict of interest. Guangjun Ma declares that he has no conflict of interest. Wei Yang declares that he has no conflict of interest.

Ethical approval

The Guide for the Care and Use of Laboratory Animals [National Research Council (US) Committee for the update of the Guide for the Care and Use of Laboratory Animals, 2011] was followed. All procedures in studies involving animals were performed in accordance with the ethical standards of the Animal Ethics Committee of the Fourth Hospital of Hebei Medical University (Shijiazhuang, Hebei Province, China).

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Jianguo Bai and Jianfei Wu equally to this study and share first authorship.

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Bai, J., Wu, J., Tang, R. et al. Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a. Invest New Drugs 38, 229–245 (2020). https://doi.org/10.1007/s10637-019-00777-5

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Keywords

  • Emodin
  • Liver cancer
  • VEGFR2
  • miR-34a