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Angiotensin II Receptor Antagonist, Valsartan, Has Beneficial Effect in Lung Metastasis of Colorectal Cancer Treated with Fluorouracil

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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.

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Data Availability

The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

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Funding

This study was supported by grants awarded by the Mashhad University of Medical Sciences.

Author information

Authors and Affiliations

  1. Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Fereshteh Asgharzadeh, Niloufar Naghibzadeh, Milad Hashemzehi & Majid Khazaei

  2. Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Fereshteh Asgharzadeh & Amir Avan

  3. Tropical and Communicable Diseases Research Center, Iranshahr University of Medical Sciences, Iranshahr, Iran

    Milad Hashemzehi

  4. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Asma Mostafapour, Seyed Mahdi Hassanian, Amir Avan & Majid Khazaei

  5. Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Seyed Mahdi Hassanian

  6. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Amir Avan

Authors
  1. Fereshteh Asgharzadeh
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  2. Niloufar Naghibzadeh
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  5. Seyed Mahdi Hassanian
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  7. Majid Khazaei
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Corresponding authors

Correspondence to Amir Avan or Majid Khazaei.

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Ethical Approval

All of the experiments were conducted in accordance with Mashhad University of Medical Science guidelines for animal experiments, and the Local Committee for Experiments with Laboratory Animals in Mashhad, Iran, gave their approval.

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The authors declare no competing interests.

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Fereshteh Asgharzadeh and Niloufar Naghibzadeh equally contributed as first author to this study.

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Asgharzadeh, F., Naghibzadeh, N., Hashemzehi, M. et al. Angiotensin II Receptor Antagonist, Valsartan, Has Beneficial Effect in Lung Metastasis of Colorectal Cancer Treated with Fluorouracil. J Gastrointest Canc 54, 126–134 (2023). https://doi.org/10.1007/s12029-021-00717-8

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