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Resibufogenin Suppresses Triple-Negative Breast Cancer Angiogenesis by Blocking VEGFR2-Mediated Signaling Pathway.

ABSTRACT: Resibufogenin (RBF), an active compound from Bufo bufonis, has been used for the treatment of multiple malignant cancers, including pancreatic cancer, colorectal cancer, and breast cancer. However, whether RBF could exert its antitumor effect by inhibiting angiogenesis remains unknown. Here, we aimed to explore the antiangiogenic activity of RBF and its underlying mechanism on human umbilical vein endothelial cell (HUVEC), and the therapeutic efficacy with regard to antiangiogenesis in vivo using two triple-negative breast cancer (TNBC) models. Our results demonstrated that RBF can inhibit the proliferation, migration, and tube formation of HUVECs in a dose-dependent manner. Spheroid sprouts were thinner and shorter after RBF treatment in vitro 3D spheroid sprouting assay. RBF also significantly suppressed VEGF-mediated vascular network formation in vivo Matrigel plug assay. In addition, Western blot analysis was used to reveal that RBF inhibited the phosphorylation of VEGFR2 and its downstream protein kinases FAK and Src in endothelial cells (ECs). Molecular docking simulations showed that RBF affected the phosphorylation of VEGFR2 by competitively binding to the ATP-bound VEGFR2 kinase domain, thus preventing ATP from providing phosphate groups. Finally, we found that RBF exhibited promising antitumor effect through antiangiogenesis in vivo without obvious toxicity. The present study first revealed the high antiangiogenic activity and the underlying molecular basis of RBF, suggesting that RBF could be a potential antiangiogenic agent for angiogenesis-related diseases.

SUBMITTER: Yang T

PROVIDER: S-EPMC8121540 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Intercellular communication is critical for integrating complex signals in multicellular eukaryotes. Vascular endothelial cells and T lymphocytes closely interact during the recirculation and trans-endothelial migration of T cells. In addition to direct cell-cell contact, we show that T cell derived extracellular vesicles can interact with endothelial cells and modulate their cellular functions. Thrombospondin-1 and its receptor CD47 are expressed on exosomes/ectosomes derived from T cells, and these extracellular vesicles are internalized and modulate signaling in both T cells and endothelial cells. Extracellular vesicles released from cells expressing or lacking CD47 differentially regulate activation of T cells induced by engaging the T cell receptor. Similarly, T cell-derived extracellular vesicles modulate endothelial cell responses to vascular endothelial growth factor and tube formation in a CD47-dependent manner. Uptake of T cell derived extracellular vesicles by recipient endothelial cells globally alters gene expression in a CD47-dependent manner. CD47 also regulates the mRNA content of extracellular vesicles in a manner consistent with some of the resulting alterations in target endothelial cell gene expression. Therefore, the thrombospondin-1 receptor CD47 directly or indirectly regulates intercellular communication mediated by the transfer of extracellular vesicles between vascular cells. Treatment with B6H12 antibody inhibited co-immunoprecipitation of EGFR with CD47 and inhibited EGF-induced EGFR tyrosine phosphorylation. B6H12 treatment of bCSC also suppressed asymmetric cell division and cell proliferation and up-regulated caspase 3/7 activity. Correspondingly, caspase-7 cleavage in human breast cancers correlated with CD47 expression. Our data shows that B6H12 specifically targets bCSCs but not differentiated cancer cells, and this CD47 signaling is independent of SIRPÎ±. Three replicates of each condition were generated. Three replicates of each MDA-231 attached cells (differentiated), MDA-231 in suspension cells (bCSC), MDA-231 in suspension cells (bCSC) treated with Control Antibody and MDA-231 in suspension cells (bCSC) treated with B6H12 Antibody.

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Resibufogenin Suppresses Triple-Negative Breast Cancer Angiogenesis by Blocking VEGFR2-Mediated Signaling Pathway.

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