Inhibition of Transforming Growth Factor-Beta by Tranilast Reduces Tumor Growth and Ameliorates Fibrosis in Colorectal Cancer Publisher



Hashemzehi M^{1, 2} ; Yavari N³ ; Rahmani F² ; Asgharzadeh F¹ ; Soleimani A⁴ ; Shakour N^{5, 6} ; Avan A^{7, 8} ; Hadizadeh F^{5, 9} ; Fakhraie M¹ ; Marjaneh RM¹ ; Ferns GA¹⁰ ; Reisi P³ ; Ryzhikov M¹¹ ; Khazaei M^{1, 7} Show All Authors Show Affiliations
Source: EXCLI Journal Published:2021

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-prolifera-tive 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. Tra-nilast 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 induct-ing ROS, thus supporting this therapeutic approach in CRC treatment. © 2021, Leibniz Research Centre for Working Environment and Human Factors. All rights reserved.