A New Approach to Inhibiting Triple-Negative Breast Cancer: In Vitro, Ex Vivo and In Vivo Antiangiogenic Effect of BthTx-II, a PLA2-Asp-49 from Bothrops jararacussu Venom

Abstract

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.

Antiproliferative activity of snake venom-derived phospholipase classes against tumor cell lines: A systematic review.

“…As main biological activities, PLA2s showed an increase in apoptosis rate in tumor cell lines [2,3,6,16,21,26]. In the studies, a reduction in the adhesion rate of tumor cell lines was also observed [2,3,4,5,19]. In addition, an increase in the rate of cell apoptosis was observed [2].…”

“…As far as possible, please keep the introduction comprehensible to scientists outside your particular field of research. References should be numbered in order of appearance and indicated by a numeral or numerals in square brackets-e.g., [1] or [2,3], or [4][5][6]. See the end of the document for further details on references.…”

DNA damage response & senescence-associated secretory phenotype pathway: Emerging targets for anti-aging

“…For example, upon cancer triggering, the amplitude of protein secretion is remarkably high compared to that of other aging-induced factors. Despite the quantitative and qualitative differences among SASP in different tissues and aging models, the main SASP structure consists of monocyte chemoattractant protein 1, CXC chemokine ligand 8, and pro-inflammatory interleukin-6 (IL-6) in all in vitrogenerated models [45]. SASP is not only a composite of proinflammatory cytokines but also enzymes involved in ECM (Extra cellular matrix) remodeling, such as tissue metalloproteinase inhibitors, cysteine/serine proteinase inhibitors, and matrix metalloproteinases.…”

In Silico Evaluation of Quercetin Methylated Derivatives on the Interaction with Secretory Phospholipases A2 from Crotalus durissus terrificus and Bothrops jararacussu

“…This toxin is considered a PLA2-like due to some characteristics, such as the Ca 2+ binding loop distortion, leading to changes in the C-terminal region. In this way, this protein shows a low phospholipase A2 activity besides to exhibit myotoxic, edematogenic, and hemolytic effects [9,10]. Bothropstoxin I (BthTX-I) is a Lys49-PLA2, which reveals high myotoxic activity with a lack of enzymatic activity.…”