Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer

Authors

  • Milad Hashemzehi Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Iranshahr University of Medical Sciences, Iranshahr, Iran; Tropical and Communicable Diseases Research Centre, Iranshahr University of Medical Sciences, Iranshahr, Iran
  • Farzad Rahmani Iranshahr University of Medical Sciences, Iranshahr, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran https://orcid.org/0000-0002-8263-0828
  • Mahdieh Khoshakhlagh Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • 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
  • Fereshteh Asgharzadeh Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran https://orcid.org/0000-0002-8349-3722
  • Farnaz Barneh Faculty of Paramedical Sciences, Beheshti University of Medical Sciences, Tehran, Iran; Current address: Princess Maxima Center for Pediatric Oncology, 3584, CS, Utrecht, The Netherlands
  • Reyhaneh Moradi-Marjaneh Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • Atena Soleimani Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • Hamid Fiuji Department of Clinical Biochemistry, Faculty 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
  • Mikhail Ryzhikov Saint Louis University, School of Medicine, St. Louis, MO, USA https://orcid.org/0000-0003-0729-1368
  • Mohieddin Jafari Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Finland https://orcid.org/0000-0002-6991-8587
  • Majid Khazaei Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Phone: (+98) 5138002227, Fax: (+98) 5138002348; E-mail: Khazaeim@mums.ac.ir https://orcid.org/0000-0002-7979-5699
  • Seyed Mahdi Hassanian Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, Phone: (+98) 5138002227, Fax: (+98) 5138002389; E-mail: HasanianmehrM@mums.ac.ir https://orcid.org/0000-0002-9486-0778

DOI:

https://doi.org/10.17179/excli2020-3083

Keywords:

colorectal cancer, Losartan, renin-angiotensin system

Abstract

The renin-angiotensin system (RAS) is up-regulated in patients with colorectal cancer (CRC) and is reported to be associated with poor prognosis and chemo-resistance. Here we explored the therapeutic potential of targeting RAS in CRC using Losartan, an angiotensin receptor blocker. An integrative-systems biology approach was used to explore a proteome-level dataset of a gene signature that is modulated by Losartan. The anti-proliferative activity of Losartan was evaluated using 2- and 3-dimensional cell culture models. A xenograft model of colon cancer was used to investigate tumor growth with Losartan alone and in combination with 5-FU followed by histological staining (Hematoxylin & Eosin and Masson trichrome staining), biochemical analyses, gene expression analyses by RT-PCR, western blot/IHC, or MMP Gelatin Zymography studies. Effects on cell cycle and cell death were assessed by flow cytometry. Losartan inhibited cell growth and suppressed cell cycle progression, causing an increase in CRC cells in the G1 phase. Losartan significantly reduced tumor growth and enhanced tumor cell necrosis. An impact on the inflammatory response, including up-regulation of pro-inflammatory cytokines and chemokines in CRC cells are potential mechanisms that could partially explain Losartan’s anti-proliferative effects. Moreover, metastasis and angiogenesis were reduced in Losartan-treated mice as observed by inhibited matrix metalloproteinase-2 and -9 activities and decreased tumor vasculature. These data demonstrate the therapeutic potential of combining chemotherapeutic regimens with Losartan to synergistically enhance its activity and target the renin-angiotensin system as a new approach in colorectal cancer treatment.

Additional Files

Published

2021-03-01

How to Cite

Hashemzehi, M. ., Rahmani, F., Khoshakhlagh, M. ., Avan, A., Asgharzadeh, F. ., Barneh, F. ., … Hassanian, S. M. (2021). Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer. EXCLI Journal, 20, 506–521. https://doi.org/10.17179/excli2020-3083

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