College of Veterinary Medicine, Chonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea.
College of Veterinary Medicine, Chonbuk National University, Iksan, Jeollabuk-do 54596, Republic of Korea.
Biomed Pharmacother. 2019 Sep;117:109091. doi: 10.1016/j.biopha.2019.109091. Epub 2019 Jun 19.
Diosmetin is a natural flavonoid obtained from citrus fruits and some medicinal herbs. Previous studies have reported the anti-cancer activity of diosmetin in some types of tumors. However, it is still unclear whether diosmetin exerts anti-cancer effects, particularly anti-angiogenic effects, in skin cancer. In this study, we used B16F10 melanoma cells and human umbilical vein endothelial cells to investigate the inhibitory effect of diosmetin on cell proliferation, migration and tube formation in vitro. Rat aorta ring assays were performed to determine the effect of diosmetin on ECs sprouting ex vivo. Furthermore, a B16F10 mouse melanoma model was used to observe the effect of diosmetin on tumor growth, angiogenesis, and metastasis in vivo. Our results showed that diosmetin not only suppressed tumor cell proliferation and migration but also induced cell apoptosis via the caspase pathway in B16F10 cells, and potently inhibited tube formation and cell migration in HUVECs. Rat aorta ring assays showed that diosmetin attenuated the ECs sprouting. Moreover, the mouse melanoma model showed that diosmetin significantly delayed tumor growth by inhibiting tumor vessels sprouting and expansion during tumor progression. Notably, diosmetin induced the normalization of tumor vasculature through the downregulation of angiopoietin-2 and the improvement of pericyte coverage, leading to suppression of metastasis formation in lungs and lymph nodes. In conclusion, our results demonstrate that diosmetin suppresses tumor progression and metastasis by inducing tumor cell death and inhibiting tumor angiogenesis as well as normalizing the defective tumor vasculature, suggesting that diosmetin is a potential adjuvant chemotherapy agent.
香叶木素是一种从柑橘类水果和一些草药中提取的天然类黄酮。先前的研究报道了香叶木素在某些类型的肿瘤中的抗癌活性。然而，香叶木素是否在皮肤癌中发挥抗癌作用，特别是抗血管生成作用，仍不清楚。在这项研究中，我们使用 B16F10 黑色素瘤细胞和人脐静脉内皮细胞（HUVEC）来研究香叶木素在体外对细胞增殖、迁移和管形成的抑制作用。进行大鼠主动脉环实验以确定香叶木素对 ECs 出芽的影响。此外，还使用 B16F10 小鼠黑色素瘤模型观察香叶木素对体内肿瘤生长、血管生成和转移的影响。我们的结果表明，香叶木素不仅抑制了 B16F10 细胞的肿瘤细胞增殖和迁移，还通过半胱天冬酶途径诱导细胞凋亡，并且强烈抑制了 HUVECs 的管形成和细胞迁移。大鼠主动脉环实验表明香叶木素减弱了 ECs 的出芽。此外，小鼠黑色素瘤模型表明香叶木素通过抑制肿瘤血管的出芽和扩张，显著延缓了肿瘤的生长，从而抑制了肺部和淋巴结转移的形成。总之，我们的结果表明，香叶木素通过诱导肿瘤细胞死亡和抑制肿瘤血管生成以及使受损的肿瘤血管正常化来抑制肿瘤的进展和转移，表明香叶木素是一种潜在的辅助化疗药物。
