Inhibition of angiotensin pathway via valsartan reduces tumor growth in models of colorectal cancer

Fereshteh Asgharzadeh, Asma Mostafapour, Safieh Ebrahimi, Forouzan Amerizadeh, Reihaneh Sabbaghzadeh, Seyed Mahdi Hassanian, Maryam Fakhraei, Alieh Farshbaf, Gordon A. Ferns, Elisa Giovannetti, Amir Avan*, Majid Khazaei*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Overexpression of the angiotensin-II receptor and renin–angiotensin system (RAS) has been reported in several malignancies, including colorectal-cancer (CRC), indicating its potential value as a therapeutic target. Here we explored the impact of targeting the RAS using an angiotensin II receptor blocker, valsartan, alone and its combination with Fluorouracil (5-FU) in in vitro and in vivo models of CRC. Methods: Anti-proliferative activity of valsartan was evaluated in 2−/3-dimensional in vitro and in vivo CRC mouse models. The anti-migratory effects of this agent was assessed by wound-healing assay, while apoptosis was studied using 4′,6-diamidino-2-phenylindole or DAPI staining, and staining with Annexin-V–fluorescein isothiocyanate with analysis using FACS. Gene-expression was determined at mRNA and protein levels. We further evaluated the anti-inflammatory properties of valsartan by histological analysis and the measurement of oxidative/antioxidant markers. Gelatin zymography was used to measure matrix metalloproteinase-2 and -9 activity (MMP-2 and 9). Results: Valsartan suppressed CRC cell-growth and synergistically enhanced the anti-tumor-activities of 5-FU by induction of apoptosis, BAX, BCL2, P53 and modulation of the cell cycle. Valsartan inhibited the cell migration by perturbation of MMP2/9. Furthermore, valsartan inhibited tumor-growth, and this was more pronounced when using the valsartan/5-FU combination. The plausible mechanism for this is via the induction of ROS and down-regulation of SOD, thiol/catalase as well as VEGF. Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory factors including interleukins and Col1A1 expression. Conclusions: Our findings demonstrated that targeting RAS pathway using Valsartan interferes with cell-proliferation, induces apoptosis, reduces migration and synergistically interacts with 5-FU, supporting further studies on this new therapeutic approach for colorectal cancer.
Original languageEnglish
Article number115951
JournalToxicology and Applied Pharmacology
Volume440
DOIs
Publication statusPublished - 1 Apr 2022

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