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. Preprints2020, 2020070508. https://doi.org/10.20944/preprints202007.0508.v1
APA Style
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. (2020). Inhibition of Angiotensin II Type I Pathway Reduced Tumor Growth and Ameliorates Fibrosis/inflammation Associated with Colorectal Cancer. Preprints. https://doi.org/10.20944/preprints202007.0508.v1
Chicago/Turabian Style
Asgharzadeh, F., William C. Cho and Majid Khazaei. 2020 "Inhibition of Angiotensin II Type I Pathway Reduced Tumor Growth and Ameliorates Fibrosis/inflammation Associated with Colorectal Cancer" Preprints. https://doi.org/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.
Keywords
Angiotensin-II Type-I receptor; renin-angiotensin system; valsartan; colorectal cancer
Subject
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
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