TY - JOUR
T1 - Inhibition of angiotensin pathway via valsartan reduces tumor growth in models of colorectal cancer
AU - Asgharzadeh, Fereshteh
AU - Mostafapour, Asma
AU - Ebrahimi, Safieh
AU - Amerizadeh, Forouzan
AU - Sabbaghzadeh, Reihaneh
AU - Hassanian, Seyed Mahdi
AU - Fakhraei, Maryam
AU - Farshbaf, Alieh
AU - Ferns, Gordon A.
AU - Giovannetti, Elisa
AU - Avan, Amir
AU - Khazaei, Majid
N1 - Funding Information: This research was partly supported by National Institute for Medical Research Development , grant No. 971176 and Mashhad University of Medical Sciences , grant No. 971798 (Majid Khazaei). Funding Information: This study was supported by National Institute for Medical Research Development , grant No. 963231 and Mashhad University of Medical Sciences , grant No. 971798 . This study was a part of a Ph.D. dissertation of Fereshteh Asgharzadeh. Publisher Copyright: © 2022 Elsevier Inc.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
KW - Angiotensin receptor blocker
KW - Colorectal cancer
KW - Combination therapy
KW - Valsartan
UR - http://www.scopus.com/inward/record.url?scp=85125434375&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.taap.2022.115951
DO - https://doi.org/10.1016/j.taap.2022.115951
M3 - Article
C2 - 35235860
SN - 0041-008X
VL - 440
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
M1 - 115951
ER -