The antitumor efficacy of monomeric disintegrin obtustatin in S-180 sarcoma mouse model
- 154 Downloads
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.
KeywordsObtustatin Sarcoma Angiogenesis VEGF
This work was made possible by the research grant # molbio 3440 from the Armenian National Science and Education Fund (ANSEF) based in New York.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
For this type of study, formal consent is not required.
- 1.Aranda-Souza M, Rossato F, Costa R, Figueira T, Castilho R, Guarniere M, Nunes E, Coelho L, Correia M, Vercesi AA (2014) Lectin from Bothrops leucurus snake venom raises cytosolic calcium levels and promotes B16-F10 melanoma necrotic cell death via mitochondrial permeability transition. Toxicon 2(82):97–103CrossRefGoogle Scholar
- 10.Dean BJF, Whitwell D (2009) Epidemiology of bone and soft-tissue sarcomas. Orthop Traumatol 23:223–230Google Scholar
- 13.Fletcher CDM, Uni KK, Mertens F (2002) Eds: World Health Organisation classification of tumours. IARC Press, Pathology and genetics Lyon, 427pGoogle Scholar
- 19.Guimarães DO, Lopes DS, Azevedo FV, Gimenes SN, Silva MA, Achê DC, Gomes MS, Vecchi L, Goulart LR, Yoneyama KA, Rodrigues RS, Rodrigues VM (2017) In vitro antitumor and antiangiogenic effects of Bothropoidin, a metalloproteinase from Bothropspauloensis snake venom. Int J Biol Macromol 97:770–777CrossRefGoogle Scholar
- 23.Ibaragi S, Shimo T, Hassan NMM, Isowa S, Kurio N, Mandai H, Kodama S, Sasaki A (2011) Induction of MMP-13 expression in bone-metastasizing cancer cells by type I collagen through integrin a1b1 and a2b1-p38 MAPK signaling. Anticancer Res 31:1307–1313Google Scholar
- 25.Liang H, Xiao J, Zhou Z, Wu J, Ge F, Li Z, Zhang H, Sun J, Li F, Liu R, Chen C (2018) Hypoxia induces miR-153 through the IRE1α-XBP1 pathway to fine tune the HIF1α/VEGFA axis in breast cancer angiogenesis. Oncogene. https://doi.org/10.1038/s41388-017-0089-8
- 29.Marcinkiewicz C, Weinreb PH, Calvete JJ, Kisiel DG, Mousa SA, Tuszynski GP, Lobb RR (2003) Obtustatin: a potent selective inhibitor of alpha1beta1 integrin in vitro and angiogenesis in vivo. Cancer Res 9:2020–2023Google Scholar
- 32.Prinholato da Silva C, Costa T, Paiva R, Cintra A, Menaldo D, Antunes L, Sampaio S (2015) Antitumor potential of the myotoxin BthTX-I from Bothrops jararacussu snake venom: evaluation of cell cycle alterations and death mechanisms induced in tumor cell lines. J Venom Anim Toxins Incl Trop Dis. https://doi.org/10.1186/s40409-015-0044-5
- 37.Vihinen P, Riikonen T, Laine A, Heino J (1996) Integrin alpha 2 beta 1 in tumorigenic human osteosarcoma cell lines regulates cell adhesion, migration, and invasion by interaction with type I collagen. Cell Growth Differ 7:439–447Google Scholar
- 38.Wang GL, Semenza GL (1993) Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 268:21513–21518Google Scholar
- 39.Wang YQ, Su J, Wu F, Lu P, Yuan LF, Yuan WE, Sheng J, Jin T (2012) Biscarbamate cross-linked polyethylenimine derivative with low molecular weight, low cytotoxicity, and high efficiency for gene delivery. Int J Nanomedicine 7:693–704Google Scholar