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Anti-cancer effect of in vivo inhibition of nitric oxide synthase in a rat model of breast cancer

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Abstract

Increased expression of nitric oxide synthase (NOS) is associated with different cancers such as cervical, breast, lung, brain, and spinal cord. Inhibition of NOS activity has been suggested as potential tool to prevent breast cancer. The anti-tumor therapeutic effect of L-nitro arginine methyl ester (L-NAME), NOS inhibitor, using in vivo models is currently under investigation. We hypothesized that L-NAME will show an anti-tumor effect by delaying a progression of breast cancer via a modulation of cell death and proliferation, and angiogenesis. We used a novel model of anti-cancer treatment by the administration of L-NAME (30 mg/kg in a day, intraperitoneal) injected every third day for five weeks to rat model of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast tumor. Concentrations of nitrite anions, polyamines, malondialdehyde, NH4+ levels, and arginase activity in the blood were decreased in DMBA + L-NAME-treated rats compared with DMBA rats. The mortality rates, tumor number, weight, and volume, as well as the histopathological grade of breast cancer were also significantly reduced. In addition, L-NAME treatment showed a delay in tumor formation, and in body weight compared with rats administrated only with DMBA. In conclusion, our data show that L-NAME is a promising anti-cancer agent to treat breast cancer, which can lead to development of anti-tumor therapeutic tools in future.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

L-NAME:

L-nitro arginine methyl ester

cGMP:

Cyclic guanosine monophosphate

DMBA:

7,12-Dimethylbenz[a]anthracene

NO:

Nitric oxide

NOHA:

NG-hydroxy-L-Arginine

NOS:

Nitric oxide synthase

eNOS:

Endothelial NOS

iNOS:

Inducible NOS

nNOS:

Neuronal NOS

VEGF:

Vascular endothelial growth factor

MMP:

Matrix metalloproteinases

TLC:

Thin-layer chromatography

IP:

Intraperitoneal administration

MDA:

Malondialdehyde

IDP:

Intraductal proliferations

D:

DMBA group

DL:

DMBA + L-NAME group,

SCC:

Spindle cell carcinoma,

ILC:

Invasive lobular carcinoma

PC – G1:

Papillary carcinoma grade 1

SC:

Sarcomatoid carcinoma

TC:

Tubular carcinoma

PLBC:

Pleomorphic lobular breast cancer,

IDC:

Invasive ductal carcinoma

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The work was supported by the Science Committee of MESCS RA, in the frames of Basic support to Research Institute of Biology, Yerevan State University, the research project No 19YR-1F042, 20TTSG-1F004, 21T-1F283 and the research grant biochem-2284 from the Yervant Terzian Armenian National Science and Education Fund (ANSEF) based in New York, USA.

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Authors and Affiliations

  1. Research Institute of Biology, Yerevan State University, Yerevan, Armenia

    Nikolay Avtandilyan, Hayarpi Javrushyan, Mikayel Ginovyan & Armen Trchounian

  2. Department of Biochemistry, Microbiology and Biotechnology, Yerevan State University, 1 Alex Manoogian, 0025, Yerevan, RA, Armenia

    Nikolay Avtandilyan & Armen Trchounian

  3. Department of Human and Animal Physiology, Yerevan State University, 0025, Yerevan, Armenia

    Anna Karapetyan

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  1. Nikolay Avtandilyan
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Contributions

All authors contributed to the study's conception and design. NA, HJ, and MG have carried out the investigations and analyzed the outcomes. NA wrote the manuscript. HJ and MG edited the manuscript. The histological alterations in breast samplings have been done by AK. AT directed the experiments and corrected and reedited the manuscript. All authors read and accepted the final version of the manuscript.

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Correspondence to Nikolay Avtandilyan.

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The authors have no relevant financial or non-financial interests to disclose.

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Animal research was approved by the National Center of Bioethics (Armenia) and according to regulations outlined in the 2010/63/EU [28].

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Avtandilyan, N., Javrushyan, H., Ginovyan, M. et al. Anti-cancer effect of in vivo inhibition of nitric oxide synthase in a rat model of breast cancer. Mol Cell Biochem 478, 261–275 (2023). https://doi.org/10.1007/s11010-022-04489-y

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