Inhibition of transforming growth factor-beta by Tranilast reduces tumor growth and ameliorates fibrosis in colorectal cancer

Authors

  • Milad Hashemzehi Department of Medical Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Tropical and Communicable Diseases Research Centre, Iranshahr University of Medical Sciences, Iranshahr, Iran https://orcid.org/0000-0003-1660-045X
  • Negar Yavari Department of Medical Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran https://orcid.org/0000-0001-8883-1543
  • Farzad Rahmani Tropical and Communicable Diseases Research Centre, Iranshahr University of Medical Sciences, Iranshahr, Iran https://orcid.org/0000-0002-8263-0828
  • Fereshteh Asgharzadeh Department of Medical Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran https://orcid.org/0000-0002-8349-3722
  • Atena Soleimani Department of Clinical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • Neda Shakour Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran https://orcid.org/0000-0002-9874-1397
  • Amir Avan Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran https://orcid.org/0000-0002-4968-0962
  • Farzin Hadizadeh Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran https://orcid.org/0000-0002-7680-8191
  • Maryam Fakhraie Department of Medical Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • Reyhaneh Moradi Marjaneh Department of Medical Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • Gordon A. Ferns Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK https://orcid.org/0000-0002-0957-8349
  • Parham Reisi Department of Medical Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran https://orcid.org/0000-0002-7552-4680
  • Mikhail Ryzhikov Saint Louis University, School of Medicine, St. Louis, MO, USA https://orcid.org/0000-0003-0729-1368
  • Majid Khazaei Department of Medical Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Phone: (+98) 5138002227, Fax: (+98) 5138002389, E-mail: KhazaeiM@mums.ac.ir https://orcid.org/0000-0002-7979-5699
  • Seyed Mahdi Hassanian Department of Clinical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Phone: (+98) 5138002375, Fax: (+98) 5138002389, E-mail: hasanianmehrm@mums.ac.ir https://orcid.org/0000-0002-9486-0778

DOI:

https://doi.org/10.17179/excli2020-2932

Keywords:

colon cancer, Tranilast, TGF pathway, angiogenesis, fibrosis

Abstract

Transforming Growth Factor-beta (TGF-β) is dysregulated in colorectal cancer and there is growing evidence that it is associated with a poor prognosis and chemo-resistance in several malignances, including CRC. In this study we have explored the therapeutic potential of targeting TGF-β using Tranilast in colon cancer. The anti-proliferative activity of Tranilast was evaluated in 2- and 3-dimensional cells. We used a xenograft model of colon cancer to investigate the activity of Tranilast alone or in combination with 5-FU on tumor growth using histological staining and biochemical studies, as well as gene expression analyses using RT-PCR and Western blotting. Tranilast alone or in combination with 5-FU inhibited tumor growth and was associated with a reduction of TGF-β expression and CD31 positive endothelial cells. Histological evaluation showed that Tranilast increased tumor necrosis and reduced tumor density and angiogenesis. Tranilast increased MDA and ROS production. It was also found that Tranilast reduced total thiol concentration and reduced SOD and catalase activity. Tranilast plus 5-FU was also found to attenuate collagen deposition, reducing tumor fibrosis in tumor xenografts. Our results show that Tranilast, a TGF inhibitor, in combination with 5-FU reduces tumor growth by inhibiting fibrosis and inducting ROS, thus supporting this therapeutic approach in CRC treatment.

Author Biographies

Milad Hashemzehi, Department of Medical Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Tropical and Communicable Diseases Research Centre, Iranshahr University of Medical Sciences, Iranshahr, Iran



Parham Reisi, Department of Medical Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

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Published

2021-03-09

How to Cite

Hashemzehi, M., Yavari, N., Rahmani, F., Asgharzadeh, F., Soleimani, A., Shakour, N., … Hassanian, S. M. (2021). Inhibition of transforming growth factor-beta by Tranilast reduces tumor growth and ameliorates fibrosis in colorectal cancer . EXCLI Journal, 20, 601–613. https://doi.org/10.17179/excli2020-2932

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Section

Original articles

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