Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Inhibition of Angiotensin II Type I Pathway Reduced Tumor Growth and Ameliorates Fibrosis/inflammation Associated with Colorectal Cancer

Version 1 : Received: 21 July 2020 / Approved: 22 July 2020 / Online: 22 July 2020 (09:49:51 CEST)

How to cite: Asgharzadeh, F.; Mostafapour, A.; Amerizadeh, F.; Avan, A.; Rahmani, F.; Sabbaghzadeh, R.; Hassanian, S.M.; Fakhraei, M.; Farshbaf, A.; Ferns, G.A.; Giovannetti, E.; Cho, W.C.; Khazaei, M. Inhibition of Angiotensin II Type I Pathway Reduced Tumor Growth and Ameliorates Fibrosis/inflammation Associated with Colorectal Cancer. Preprints 2020, 2020070508 (doi: 10.20944/preprints202007.0508.v1). Asgharzadeh, F.; Mostafapour, A.; Amerizadeh, F.; Avan, A.; Rahmani, F.; Sabbaghzadeh, R.; Hassanian, S.M.; Fakhraei, M.; Farshbaf, A.; Ferns, G.A.; Giovannetti, E.; Cho, W.C.; Khazaei, M. Inhibition of Angiotensin II Type I Pathway Reduced Tumor Growth and Ameliorates Fibrosis/inflammation Associated with Colorectal Cancer. Preprints 2020, 2020070508 (doi: 10.20944/preprints202007.0508.v1).

Abstract

Dysregulation of the angiotensin-II Type-I receptor (AT1R) and its pathway was reported to associate with poor-prognosis in several malignancies, including colorectal-cancer (CRC). We have explored the therapeutic-potential of targeting AT1R using valsartan, and its pharmacological-interaction with Fluorouracil (5-FU) in CRC. Anti-proliferative function was evaluated in 2-/3-dimensional cells and in vivo models. Anti-proliferative, anti-migratory, apoptotic function and effect on cell-cycle was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound-healing test, and Fluorescence-activated cell sorting (FACS), respectively, while gene-expression was determined at mRNA/protein levels. By histogical analysis and measuring of oxidative/antioxidant markers, we evaluated the anti-inflammatory properties of valsartan. Valsartan suppressed cell-growth and impacted the anti-tumor-activities of 5-FU by apoptosis-induction. Valsartan inhibited the cells migration by perturbation of Matrix metalloproteinase (MMP1). Furthermore, valsartan inhibited tumor-growth and metastasis, and this was more notable in valsartan/5-FU combination-treated-group. The mechanism was plausible to be via the induction of Reactive-oxygen-species (ROS) and down-regulation of Superoxide-dismutase (SOD), thiol/catalase (CAT) as well as Vascular endothelial growth factor (VEGF) and Transforming growth factor beta (TGF-β). Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory components include fibronectin, Interleukin) IL-1β (, Tumor necrosis factor alpha) TNF-α (, Interferon gamma) INF-γ (, and Monocyte Chemotactic Protein 1 (MCP-1). Our findings demonstrated that targeting the AT1R receptor may inhibit tumor-growth and ameliorate fibrosis and inflammation associated with CRC via modulation of AT1 and TGF-β pathways.

Subject Areas

Angiotensin-II Type-I receptor; renin-angiotensin system; valsartan; colorectal cancer

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