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The antitumor efficacy of monomeric disintegrin obtustatin in S-180 sarcoma mouse model

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Summary

Obtustatin, isolated from the Levantine Viper snake venom (Macrovipera lebetina obtusa -MLO), is the shortest known monomeric disintegrin shown to specifically inhibit the binding of the α1β1 integrin to collagen IV. Its oncostatic effect is due to the inhibition of angiogenesis, likely through α1β1 integrin inhibition in endothelial cells. To explore the therapeutic potential of obtustatin, we studied its effect in S-180 sarcoma-bearing mice model in vivo as well as in human dermal microvascular endothelial cells (HMVEC-D) in vitro, and tested anti-angiogenic activity in vivo using the chick embryo chorioallantoic membrane assay (CAM assay). Our in vivo results show that obtustatin inhibits tumour growth by 33%. The expression of vascular endothelial growth factor (VEGF) increased after treatment with obtustatin, but the level of expression of caspase 8 did not change. In addition, our results demonstrate that obtustatin inhibits FGF2-induced angiogenesis in the CAM assay. Our in vitro results show that obtustatin does not exhibit cytotoxic activity in HMVEC-D cells in comparison to in vivo results. Thus, our findings disclose that obtustatin might be a potential candidate for the treatment of sarcoma in vivo with low toxicity.

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Funding

This work was made possible by the research grant # molbio 3440 from the Armenian National Science and Education Fund (ANSEF) based in New York.

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Authors and Affiliations

  1. Laboratory of Toxinology and Molecular Systematics, L.A. Orbeli Institute of Physiology, 0028, Yerevan, Armenia

    Narine Ghazaryan & Naira Ayvazyan

  2. Oncophysiology Group, Max Planck Institute for Experimental Medicine, 37075, Göttingen, Germany

    Narine Ghazaryan, Naira Movsisyan & Luis Pardo

  3. Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, Göttingen, Germany

    Naira Movsisyan

  4. Aging and Aneuploidy Laboratory, Instituto de Biologia Molecular e Celular, Instituto de Investigação e Inovação em Saúde – i3S, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal

    Joana Catarina Macedo, Sara Vaz & Elsa Logarinho

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  1. Narine Ghazaryan
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Correspondence to Narine Ghazaryan.

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Ghazaryan, N., Movsisyan, N., Macedo, J.C. et al. The antitumor efficacy of monomeric disintegrin obtustatin in S-180 sarcoma mouse model. Invest New Drugs 37, 1044–1051 (2019). https://doi.org/10.1007/s10637-019-00734-2

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