Arbidol inhibits human esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase

  1. Ning Yang
  2. Xuebo Lu
  3. Yanan Jiang
  4. Lili Zhao
  5. Donghao Wang
  6. Yaxing Wei
  7. Yin Yu
  8. Myoung Ok Kim
  9. Kyle Vaughn Laster
  10. Xin Li
  11. Baoyin Yuan
  12. Zigang Dong  Is a corresponding author
  13. Kangdong Liu  Is a corresponding author
  1. Zhengzhou University, China
  2. Kyungpook National University, Republic of Korea
  3. China-US Hormel Cancer Institute, China

Abstract

Human esophageal cancer has a global impact on human health due to its high incidence and mortality. Therefore, there is an urgent need to develop new drugs to treat or prevent the prominent pathological subtype of esophageal cancer, esophageal squamous cell carcinoma. Based upon a screening of drugs approved by the Food and Drug Administration, we discovered that Arbidol could effectively inhibit the proliferation of human esophageal squamous cell carcinoma in vitro. Next, we conducted a series of cell-based assays and found that Arbidol treatment inhibited the proliferation and colony formation ability of ESCC cells and promoted G1 phase cell cycle arrest. Phospho-proteomics experiments, in vitro kinase assays and pull-down assays were subsequently performed in order to identify the underlying growth inhibitory mechanism. We verified Arbidol is a potential ATR inhibitor via binding to ATR kinase to reduce the phosphorylation and activation of MCM2 at Ser108. Finally, we demonstrated Arbidol had the inhibitory effect of ESCC in vivo by a PDX model. All together, Arbidol inhibits the proliferation of ESCC in vitro and in vivo through the DNA replication pathway and is associated with the cell cycle.

Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD034944.

The following data sets were generated

Article and author information

Author details

  1. Ning Yang

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Xuebo Lu

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yanan Jiang

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Lili Zhao

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Donghao Wang

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yaxing Wei

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yin Yu

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Myoung Ok Kim

    Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  9. Kyle Vaughn Laster

    China-US Hormel Cancer Institute, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Xin Li

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Baoyin Yuan

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Zigang Dong

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    For correspondence
    dongzg@zzu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  13. Kangdong Liu

    Department of Pathophysiology, Zhengzhou University, Zhengzhou, China
    For correspondence
    kdliu@zzu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4425-5625

Funding

National Natural Science Foundation of China (81872335)

  • Kangdong Liu

National Natural Science Youth Foundatio of China (81902486)

  • Yanan Jiang

Natural Science Foundation of Henan (161100510300)

  • Kangdong Liu

The Central Plains Science and Technology Innovation Leading Talents (224200510015)

  • Kangdong Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Compliance with Ethics RequirementsIn this study, we established an ESCC PDX model. In this model, the tumor sample from an ESCC patient was EG20 (ESCC, male, T2N0M0II, moderately differentiated, obtained from Linzhou Cancer Hospital, Henan Province, China). The patient was fully informed of the study and provided consent. This study was approved by the Ethics Committee of Zhengzhou University (ZZUHCI-2019012).

Reviewing Editor

  1. Wafik S El-Deiry, Brown University, United States

Publication history

  1. Received: September 16, 2021
  2. Preprint posted: February 18, 2022 (view preprint)
  3. Accepted: September 8, 2022
  4. Accepted Manuscript published: September 9, 2022 (version 1)
  5. Version of Record published: September 26, 2022 (version 2)

Copyright

© 2022, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ning Yang
  2. Xuebo Lu
  3. Yanan Jiang
  4. Lili Zhao
  5. Donghao Wang
  6. Yaxing Wei
  7. Yin Yu
  8. Myoung Ok Kim
  9. Kyle Vaughn Laster
  10. Xin Li
  11. Baoyin Yuan
  12. Zigang Dong
  13. Kangdong Liu
(2022)
Arbidol inhibits human esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase
eLife 11:e73953.
https://doi.org/10.7554/eLife.73953

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