Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
College of Food Science and Engineering, Jilin University, Changchun, China.
Pharmacol Res. 2022 Jan;175:105983. doi: 10.1016/j.phrs.2021.105983. Epub 2021 Nov 23.
Angiogenesis plays an important role in the growth and metastasis of solid tumors including melanoma. Inhibiting tumor-associated angiogenesis is a tactic in treating melanoma. Dioscin restrains angiogenesis in colon tumor and has anti-melanoma effects in cell and animal models. In a previous study, we found that dioscin inhibits Src/STAT3 signaling in melanoma cells. Activation of the Src/STAT3 pathway has been shown to promote tumor angiogenesis. This study aimed to determine whether dioscin's anti-melanoma effects is related to inhibiting Src/STAT3 signaling-mediated angiogenesis. In a B16F10 allograft mouse model, we found that dioscin inhibited melanoma growth and angiogenesis. To exclude the impact of tumor growth on angiogenesis, a chicken chorioallantoic membrane (CAM) model was used to verify the anti-angiogenic effect of dioscin. Results showed that dioscin suppressed vessel formation in CAM. To determine if tumor secreted pro-angiogenic cytokines are involved in the anti-angiogenic effect of dioscin, conditioned media from dioscin-treated A375 melanoma cells were used to culture human umbilical vein endothelial cells (HUVECs), and tube formation was monitored. It was observed that the tube formation of HUVECs was inhibited. Mechanistic studies revealed that dioscin inhibited the activation of Src and STAT3, and lowered mRNA and protein levels of STAT3 transcriptionally-regulated genes, in B16F10 melanomas. ELISA assays showed that dioscin decreased the secretion of MMP-2, MMP-9 and VEGF from A375 cells. Over-activation of STAT3 lessened the effects of dioscin in decreasing the secretion of pro-angiogenic cytokines from melanoma cells, and in inhibiting tube formation of HUVECs cultured with conditioned media from melanoma cell cultures. In summary, we for the first time demonstrated that inhibiting Src/STAT3 signaling-mediated angiogenesis is involved in the anti-melanoma effects of dioscin. This study provides further pharmacological groundwork for developing dioscin as an anti-melanoma agent.
血管生成在包括黑色素瘤在内的实体瘤的生长和转移中起着重要作用。抑制肿瘤相关的血管生成是治疗黑色素瘤的一种策略。薯蓣皂甙抑制结肠肿瘤中的血管生成，并在细胞和动物模型中具有抗黑色素瘤作用。在之前的一项研究中，我们发现薯蓣皂甙抑制黑色素瘤细胞中的Src/STAT3 信号通路。Src/STAT3 通路的激活已被证明可促进肿瘤血管生成。本研究旨在确定薯蓣皂甙的抗黑色素瘤作用是否与抑制 Src/STAT3 信号通路介导的血管生成有关。在 B16F10 同种异体移植小鼠模型中，我们发现薯蓣皂甙抑制黑色素瘤生长和血管生成。为了排除肿瘤生长对血管生成的影响，使用鸡胚尿囊膜 (CAM) 模型验证薯蓣皂甙的抗血管生成作用。结果表明，薯蓣皂甙抑制 CAM 中的血管形成。为了确定肿瘤分泌的促血管生成细胞因子是否参与薯蓣皂甙的抗血管生成作用，用薯蓣皂甙处理的 A375 黑色素瘤细胞的条件培养基来培养人脐静脉内皮细胞 (HUVECs)，并监测管形成情况。观察到 HUVECs 的管形成被抑制。机制研究表明，薯蓣皂甙抑制 Src 和 STAT3 的激活，并降低 B16F10 黑色素瘤中 STAT3 转录调节基因的 mRNA 和蛋白水平。ELISA 检测表明，薯蓣皂甙降低 A375 细胞分泌的 MMP-2、MMP-9 和 VEGF。STAT3 的过度激活减弱了薯蓣皂甙降低黑色素瘤细胞分泌促血管生成细胞因子和抑制用黑色素瘤细胞培养物的条件培养基培养的 HUVECs 管形成的作用。总之，我们首次证明抑制 Src/STAT3 信号通路介导的血管生成参与了薯蓣皂甙的抗黑色素瘤作用。本研究为将薯蓣皂甙开发为抗黑色素瘤药物提供了进一步的药理学基础。
