A New Approach to Inhibiting Triple-Negative Breast Cancer: In Vitro, Ex Vivo and In Vivo Antiangiogenic Effect of BthTx-II, a PLA<sub>2</sub>-Asp-49 from <i>Bothrops jararacussu</i> Venom
Fernanda Van Petten de Vasconcelos Azevedo,
Daiana Silva Lopes,
Mariana Alves Pereira Zóia,
Lucas Ian Veloso Correia,
Natieli Saito,
Belchiolina Beatriz Fonseca,
Lorena Polloni,
Samuel Cota Teixeira,
Luiz Ricardo Goulart,
Veridiana de Melo Rodrigues Ávila
Affiliations
Fernanda Van Petten de Vasconcelos Azevedo
Laboratory of Biochemistry and Animal Toxins, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil
Daiana Silva Lopes
Multidisciplinary Institute of Health, Federal University of Bahia, Vitoria da Conquista, Salvador 40170-110, BA, Brazil
Mariana Alves Pereira Zóia
Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil
Lucas Ian Veloso Correia
Laboratory of Biochemistry and Animal Toxins, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil
Natieli Saito
Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil
Belchiolina Beatriz Fonseca
College of Veterinary Medicine, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil
Lorena Polloni
Laboratory of Biochemistry and Animal Toxins, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil
Samuel Cota Teixeira
Department of Immunology, Biomedical Sciences Institute, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil
Luiz Ricardo Goulart
Laboratory of Nanobiotechnology, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil
Veridiana de Melo Rodrigues Ávila
Laboratory of Biochemistry and Animal Toxins, Institute of Biotechnology, Federal University of Uberlandia, Uberlândia 38408-100, MG, Brazil
Phospholipases A2 (PLA2) represent a superfamily of enzymes widely distributed in living organisms, with a broad spectrum of pharmacological activities and therapeutic potential. Anti-angiogenic strategies have become one of the main tools in fighting cancer. In this sense, the present work reports the inhibition of tumor angiogenesis induced by Asp-49 BthTX-II using in vitro, ex vivo and in vivo approaches. We demonstrate that BthTx-II inhibited cell adhesion, proliferation, and migration of human umbilical vein endothelial cells (HUVEC), as well as caused a reduction in the levels of endothelial growth factor (VEGF) during in vitro angiogenesis assays. BthTx-II was also able to inhibit the sprouting angiogenic process, by the ex vivo germination assay of the aortic ring; in addition, this toxin inhibited the migration and proliferation of HUVEC in co-culture with triple-negative breast cancer cells (e.g., MDA-MB-231 cells). Finally, in vivo tumor suppression and anti-angiogenic activities were analyzed using MDA-MB-231 cells with Matrigel injected into the chorioallantoic membrane of chicken embryo (CAM) for 7 days treatment with BthTx-II, showing a considerable reduction in vessel caliber, on the size and weight of tumors. Together, these results suggest an important antiangiogenic and antitumor role for BthTx-II, as a potential prototype for the development of new tools and antitumor drugs in cancer therapy.
