Inhibition of angiotensin II type 1 receptor by candesartan reduces tumor growth and ameliorates fibrosis in colorectal cancer

Main Article Content

Ehsan Tabatabai
Majid Khazaei
Fereshteh Asgharzadeh
Seyedeh Elnaz Nazari
Neda Shakour
Hamid Fiuji
Aghigh Ziaeemehr
Asma Mostafapour
Mohammad Reza Parizadeh
Mohammad Nouri
Seyed Mahdi Hassanian
Farzin Hadizadeh
Gordon A. Ferns
Mohammad Rahmati
Farzad Rahmani
Amir Avan

Abstract

Colorectal cancer (CRC) is an important cause of cancer-related mortality. Aberrant activation of the renin-angiotensin system (RAS) is reported to be associated with poor clinical outcomes in patients with CRC. This study was designed to explore the anti-tumor effects of the angiotensin receptor blocker Candesartan either alone or in combination with 5-FU in in vitro and in vivo models of CRC. The cytotoxic effects of Candesartan were assessed using the MTT assay in two colorectal cancer cell lines (CT-26 and SW-480). To investigate the potential regulatory role of Candesartan on tumor growth, apoptosis, and migration, the expression levels of Cyclin D1, Survivin, MMP3, MMP9, and E-cadherin mRNAs were evaluated. The oxidant/antioxidant balance was also examined by determining the levels of MDA, thiols, SOD, and CAT. We used a xenograft model of colon cancer to investigate the effects of Candesartan alone, or in combination with 5-FU, on tumor growth following histological staining (Hematoxylin & Eosin and Masson trichrome staining) and biochemical studies as well as gene expression analyses by RT-PCR and western blotting. Candesartan suppressed tumor cell proliferation and migration by modulating Cyclin D1, MMP3/9, and E-cadherin. Treatment with Candesartan either alone, or in combination with 5-FU decreased tumor size in the mouse model, and also increased the level of oxidative markers MDA and reduced CAT, SOD, and thiols. Histological evaluation showed that Candesartan increased tumor necrosis, reduced tumor density and attenuated collagen deposition reducing tumor fibrosis in tumor xenograft. Candesartan, an inhibitor of the RAS, when used in combination with 5-FU reduced tumor growth by inhibiting fibrosis and inducing ROS production, supporting further clinical studies on this therapeutic approach for treatment of CRC.

Article Details

How to Cite
Tabatabai, E. ., Khazaei, M., Asgharzadeh, F. ., Nazari, S. E. ., Shakour, N. ., Fiuji, H., Ziaeemehr, A., Mostafapour, A. ., Parizadeh, M. R. ., Nouri, M. ., Hassanian, S. M., Hadizadeh, F. ., Ferns, G. A., Rahmati, M. ., Rahmani, F., & Avan, A. (2021). Inhibition of angiotensin II type 1 receptor by candesartan reduces tumor growth and ameliorates fibrosis in colorectal cancer . EXCLI Journal, 20, 863-878. https://doi.org/10.17179/excli2021-3421
Section
Original articles
Author Biography

Amir Avan, Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

http://orcid.org/0000-0001-8974-2120 (diese von ihm genannt, führt aber zu

shahrokh naseri), geändert auf https://orcid.org/0000-0002-4968-0962

Most read articles by the same author(s)