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.
Highlights
IntroductionBreast cancer is the leading cause of cancer death among women worldwide and new cases are increasing each year, according to the National Center for Health Statistics [1]
MTT assay. (C) Effects of BthTx-II (1, 10, 25, and 50 μg/mL) on proliferation of human umbilical vein endothelial cells (HUVEC) for 24, 48 and 72 h of treatment, and the table on the side shows the statistical values for each treatment in relation to the positive control
It has been reported that BthTx-II inhibits the migration, adhesion, and invasion of TBNC cells in the integrin-mediated cell cycle and interferes with the epithelial–mesenchymal transition process of highly metastatic breast tumor cells (MDA-MB-231 cells) by reducing the expression of important genes and proteins related to the metastatic process, such as CK-5, Vimentin, CTNNB1, and TWIST1, and by increasing
Summary
Breast cancer is the leading cause of cancer death among women worldwide and new cases are increasing each year, according to the National Center for Health Statistics [1]. It is considered a heterogeneous disease with different distinct subtypes that respond differently to pharmacological therapy with variable rates of failure and mortality, and this issue may be associated with the capacity of formation of new vessels and tumor metastasis [2]. Angiogenesis plays a critical role in a variety of pathological conditions, and we have already reported on how Biomolecules 2022, 12, 258.
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