Abstract
Angiogenesis plays an important role in the development of multiple myeloma (MM). Baohuoside I (BI) is a core flavonoid monomer with anticancer property. However, the mechanism of BI on MM-stimulated angiogenesis has not been revealed. In this study, we demonstrated that BI inhibits MM-induced angiogenesis in vitro and angiogenesis in a xenograft mouse model in vivo. We further showed that peroxisome proliferator–activated receptor γ (PPARγ) transcriptional activity was mediated by a direct physical association between BI and PPARγ. Meanwhile, inhibition of PPARγ using lentivirus transfection of shRNA in human myeloma cell lines showed that the facilitation of PPARγ blocked angiogenesis and PPARγ repressed vascular endothelial growth factor (VEGF) transcription. Furthermore, BI treatment decreased VEGF expression, whereas VEGF expression remained unchanged after PPARγ knockdown when exposed to BI. Overall, our study is the first to reveal that BI inhibits MM angiogenesis by the PPARγ–VEGF signaling axis.
Highlights
MM is an incurable disease characterized by malignant bone marrow (BM) plasma cell infiltration
We investigated the effects of Baohuoside I (BI) on human umbilical vein endothelial cells (HUVECs) using BI-treated MM cell supernatants
Given that BI can inhibit angiogenesis and bind to peroxisome proliferator–activated receptor γ (PPARγ), we further explored the relationship between BI, PPARγ, and vascular endothelial growth factor (VEGF)
Summary
MM is an incurable disease characterized by malignant bone marrow (BM) plasma cell infiltration. Lenalidomide, an immunomodulatory drug (IMiD), is widely used to treat patients with MM, whose mechanisms are multifactorial and include angiogenesis inhibition (Holstein and McCarthy 2017). Vascular endothelial growth factor (VEGF) plays an important role in maintaining angiogenesis; during the progression of myeloma, VEGFs trigger the angiogenic switch (Hong Wang et al, 2021; Zhiyao Wang et al, 2021) by stimulating vascular permeability and endothelial cell migration and proliferation. VEGF has the ability to migrate epithelial cells from the microenvironment to the vicinity of the tumors and promotes the progression of cancers in some tumors, including lung adenocarcinoma (Jung et al, 2021), lymphoma (Shahini et al, 2017), and leukemia (Wang et al, 2015). Antiangiogenic inhibitors block the VEGF pathway and have been widely used in the clinical treatment of tumors. Bevacizumab is a monoclonal antibody against VEGF, which has been successfully used as the first-line treatment for several cancers (Ferrara et al, 2005)
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