Fereshteh Asgharzadeh1,2, Niloufar Naghibzadeh1, Milad Hashemzehi1,3, Asma Mostafapour4, Seyed Mahdi Hassanian4,5, Amir Avan6,7,8, Majid Khazaei9,10. 1. Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 2. Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 3. Tropical and Communicable Diseases Research Center, Iranshahr University of Medical Sciences, Iranshahr, Iran. 4. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. 5. Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 6. Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Avana@mums.ac.ir. 7. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Avana@mums.ac.ir. 8. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Avana@mums.ac.ir. 9. Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. KhazaeiM@mums.ac.ir. 10. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. KhazaeiM@mums.ac.ir.
Abstract
PURPOSE: Lung metastasis is the main cause of death in patients with colorectal carcinoma (CRC). Angiotensin II has been confirmed to facilitate cancer cell progression and metastasis. In this study, the possible anti-metastatic effects of an angiotensin II receptor type 1 (AT1R) antagonist, valsartan, have been investigated in an experimental CRC lung metastasis model. METHODS: An animal CRC lung metastasis model was used, involving intravenous injection of CRC cells. The experimental groups included (1) control group; (2) 5-FU (5-fluorouracil) group (5 mg/kg/every other day; ip); (3) valsartan group (40 mg/kg/day; po); and (4) valsartan + 5-FU group (combination group; valsartan 40 mg/kg/day, oral gavage, and 5-FU 5 mg/kg/every other day; ip). After 11 days, macroscopic and histological evaluations of lung tissues have been done for evaluation of lung metastatic nodules. In addition, inflammatory and angiogenic markers and oxidative stress index were measured in lung tissue. RESULTS: Our results showed that administration of valsartan especially in combination with 5-FU significantly reduced lung metastatic nodule and metastatic area (p < 0.05) in macroscopic and histological evaluations stained by hematoxylin-eosin. Measurement of inflammatory, angiogenic, and oxidative/antioxidative markers in lung tissue indicated that the level of IL-6, angiogenic markers (VEGF and VEGFR-1), and antioxidative markers significantly reduced in combination group (p < 0.05) while the MDA as a marker of oxidative stress increased (p < 0.05). CONCLUSION: These results suggest that valsartan in combination with standard chemotherapeutic agents can have a synergistic effect in treatment of lung metastasis of CRC.
PURPOSE: Lung metastasis is the main cause of death in patients with colorectal carcinoma (CRC). Angiotensin II has been confirmed to facilitate cancer cell progression and metastasis. In this study, the possible anti-metastatic effects of an angiotensin II receptor type 1 (AT1R) antagonist, valsartan, have been investigated in an experimental CRC lung metastasis model. METHODS: An animal CRC lung metastasis model was used, involving intravenous injection of CRC cells. The experimental groups included (1) control group; (2) 5-FU (5-fluorouracil) group (5 mg/kg/every other day; ip); (3) valsartan group (40 mg/kg/day; po); and (4) valsartan + 5-FU group (combination group; valsartan 40 mg/kg/day, oral gavage, and 5-FU 5 mg/kg/every other day; ip). After 11 days, macroscopic and histological evaluations of lung tissues have been done for evaluation of lung metastatic nodules. In addition, inflammatory and angiogenic markers and oxidative stress index were measured in lung tissue. RESULTS: Our results showed that administration of valsartan especially in combination with 5-FU significantly reduced lung metastatic nodule and metastatic area (p < 0.05) in macroscopic and histological evaluations stained by hematoxylin-eosin. Measurement of inflammatory, angiogenic, and oxidative/antioxidative markers in lung tissue indicated that the level of IL-6, angiogenic markers (VEGF and VEGFR-1), and antioxidative markers significantly reduced in combination group (p < 0.05) while the MDA as a marker of oxidative stress increased (p < 0.05). CONCLUSION: These results suggest that valsartan in combination with standard chemotherapeutic agents can have a synergistic effect in treatment of lung metastasis of CRC.