Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer

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Milad Hashemzehi
Farzad Rahmani
Mahdieh Khoshakhlagh
Amir Avan
Fereshteh Asgharzadeh
Farnaz Barneh
Reyhaneh Moradi-Marjaneh
Atena Soleimani
Hamid Fiuji
Gordon A. Ferns
Mikhail Ryzhikov
Mohieddin Jafari
Majid Khazaei
Seyed Mahdi Hassanian

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.

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How to Cite
Hashemzehi, M. ., Rahmani, F., Khoshakhlagh, M. ., Avan, A., Asgharzadeh, F. ., Barneh, F. ., Moradi-Marjaneh, R. ., Soleimani, A. ., Fiuji, H. ., Ferns, G. A., Ryzhikov, M. ., Jafari, M. ., Khazaei, M., & 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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Original articles

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