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

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Milad Hashemzehi
Negar Yavari
Farzad Rahmani
Fereshteh Asgharzadeh
Atena Soleimani
Neda Shakour
Amir Avan
Farzin Hadizadeh
Maryam Fakhraie
Reyhaneh Moradi Marjaneh
Gordon A. Ferns
Parham Reisi
Mikhail Ryzhikov
Majid Khazaei
Seyed Mahdi Hassanian

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.

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How to Cite
Hashemzehi, M., Yavari, N., Rahmani, F., Asgharzadeh, F., Soleimani, A., Shakour, N., Avan, A., Hadizadeh, F., Fakhraie, M., Moradi Marjaneh, R., Ferns, G. A., Reisi, P., Ryzhikov, M., Khazaei, M., & 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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Original articles
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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