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Vactosertib potently improves anti-tumor properties of 5-FU for colon cancer

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Abstract

Background

Several studies have shown that the TGF-β signaling pathway plays a critical role in colorectal cancer (CRC) pathogenesis. The aim of the current study is to investigate the therapeutic potential of Vactosertib (EW-7197), a selective inhibitor of TGF-β receptor type I, either alone or in combination with the standard first-line chemotherapeutic treatment, 5-Fluorouracil (5-FU), in CRC progression in both cellular and animal models.

Methods

Real-Time PCR, Zymography, enzyme-linked immunosorbent assay (ELISA), Hematoxylin and Eosin (H&E) tissue staining, and Flow cytometry techniques were applied to determine the anti-tumor properties of this novel TGF-β inhibitor in in vitro (CT-26 cell line) and in vivo (inbred BALB/C mice) samples.

Results

Our findings showed that Vactosertib decreased cell proliferation and induced spheroid shrinkage. Moreover, this inhibitor suppressed the cell cycle and its administration either alone or in combination with 5-FU induced apoptosis by regulating the expression of p53 and BAX proteins. It also improved 5-FU anti-cancer effects by decreasing the tumor volume and weight, increasing tumor necrosis, and regulating tumor fibrosis and inflammation in an animal model. Vactosertib also enhanced the inhibitory effect of 5-FU on invasive behavior of CRC cells by upregulating the expression of E-cadherin and inhibiting MMP-9 enzymatic activity.

Conclusion

This study demonstrating the potent anti-tumor effects of Vactosertib against CRC progression. Our results clearly suggest that this inhibitor could be a promising agent reducing CRC tumor progression when administered either alone or in combination with standard treatment in CRC patients.

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Data availability

All data are available from the corresponding author on reasonable request.

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Funding

This study supported by grants awarded by the Biotechnology Development Council of the Islamic Republic of Iran (Grant No. 970306) and Iran National Science Foundation (Grant No. 97014095).

Author information

Author notes

  1. Maryam Moradi Binabaj, Fereshteh Asgharzadeh, Farzad Rahmani and Milad Hashemzehi contributed equally to this work.

Authors and Affiliations

  1. Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran

    Maryam Moradi Binabaj

  2. Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Maryam Moradi Binabaj, Atena Soleimani & Seyed Mahdi Hassanian

  3. Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Fereshteh Asgharzadeh & Majid Khazaei

  4. Kashmar School of Nursing, Mashhad University of Medical Sciences, Mashhad, Iran

    Farzad Rahmani

  5. Department of Medical Sciences, Faculty of Nursing, University of Warith Al-Anbiyaa, Kerbala, Iraq

    Abdulridha Mohammed Al-Asady

  6. Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Abdulridha Mohammed Al-Asady

  7. Department of Medical Sciences, Faculty of Dentistry, University of Kerbala, Kerbala, Iraq

    Abdulridha Mohammed Al-Asady

  8. Iranshahr University of Medical Sciences, Iranshahr, Iran

    Milad Hashemzehi

  9. Department of Human Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Amir Avan

  10. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Amir Avan, Majid Khazaei & Seyed Mahdi Hassanian

  11. Immunology Research Center, Inflammation and Inflammatory Diseases Division, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Saeedeh Mehraban

  12. Department of Medical Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Elnaz Ghorbani

  13. School of Medicine, Saint Louis University, St. Louis, MO, USA

    Mikhail Ryzhikov

Authors
  1. Maryam Moradi Binabaj
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  2. Fereshteh Asgharzadeh
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  4. Abdulridha Mohammed Al-Asady
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  5. Milad Hashemzehi
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  6. Atena Soleimani
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  11. Majid Khazaei
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Contributions

M.M.B and F.A. initiated, designed and executed the animal experiments and finally drafted the manuscript. F.R. and A.M.A.A. performed the cellular experiments. The oxidation stress tests were done by M.H., AA, R. H., and S.M. partially contributed in executing the project. E.G and M.R edited and reviewed the manuscript. AA was a consultant of this project and also supervised cellular experiments. MK and S.M.H supervised the whole project including the study and performed experiments. They also provided all the chemicals. “The authors declare that all data were generated in-house and that no paper mill was used”.

Corresponding authors

Correspondence to Majid Khazaei or Seyed Mahdi Hassanian.

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Ethics approval and consent to participate

All animal experiments were carried out in accordance with the guidelines of National Institute of Health for the Care and Use of Laboratory Animals (NIH Publication No. 80–23; revised 1978) and were approved by the Ethics Committee of Mashhad University of Medical Sciences. All methods are reported in accordance with ARRIVE guidelines for the reporting of animal experiments.

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Binabaj, M.M., Asgharzadeh, F., Rahmani, F. et al. Vactosertib potently improves anti-tumor properties of 5-FU for colon cancer. DARU J Pharm Sci 31, 193–203 (2023). https://doi.org/10.1007/s40199-023-00474-y

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