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

Authors

  • Ehsan Tabatabai Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran http://orcid.org/0000-0001-9905-4516
  • Majid Khazaei Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran http://orcid.org/0000-0002-7979-5699
  • Fereshteh Asgharzadeh Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran http://orcid.org/0000-0002-8349-3722
  • Seyedeh Elnaz Nazari Department of Physiology, Faculty 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 http://orcid.org/0000-0002-9874-1397
  • Hamid Fiuji Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
  • Aghigh Ziaeemehr Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
  • Asma Mostafapour Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran http://orcid.org/0000-0001-8337-2827
  • Mohammad Reza Parizadeh Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran http://orcid.org/0000-0003-4532-4546
  • Mohammad Nouri Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran http://orcid.org/0000-0002-5367-9956
  • Seyed Mahdi Hassanian Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran http://orcid.org/0000-0002-5247-4043
  • 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 http://orcid.org/0000-0002-7680-8191
  • Gordon A. Ferns Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK http://orcid.org/0000-0002-0957-8349
  • Mohammad Rahmati Department of Clinical Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. E-mail: Rahmatibio@gmail.com http://orcid.org/0000-0002-0971-0813
  • Farzad Rahmani Iranshahr University of Medical Sciences, Iranshahr, Iran. E-mail: Rahmany.farzad@gmail.com http://orcid.org/0000-0002-8263-0828
  • Amir Avan Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran https://orcid.org/0000-0002-4968-0962

DOI:

https://doi.org/10.17179/excli2021-3421

Keywords:

candesartan, colorectal cancer, renin-angiotensin system

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.

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

Additional Files

Published

2021-05-07

How to Cite

Tabatabai, E. ., Khazaei, M., Asgharzadeh, F. ., Nazari, S. E. ., Shakour, N. ., Fiuji, H., … 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

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Original articles

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