Alantolactone inhibits proliferation, metastasis and promotes apoptosis of human osteosarcoma cells by suppressing Wnt/β-catenin and MAPKs signaling pathways.
Alantolactone inhibits proliferation, metastasis and promotes apoptosis of human osteosarcoma cells by suppressing Wnt/β-catenin and MAPKs signaling pathways.
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Alantolactone 通过抑制 Wnt/β-catenin 和 MAPKs 信号通路抑制人骨肉瘤细胞的增殖、转移并促进细胞凋亡
DOI：
10.1016/j.gendis.2020.07.014
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发表时间：
2022-03
期刊：
影响因子：
6.8
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Yang C;Zhang L;Huang H;Yuan X;Zhang P;Ye C;Wei M;Huang Y;Luo X;Luo J
尽管目前已有手术、化疗等多种治疗手段，但骨肉瘤的预后仍不理想。本研究以香旋覆花（Inula helenium）为原料，研究香木香内酯（Alantolactone，ALT）的抗OS活性，并探讨其可能的作用机制。我们证明ALT显著抑制各种人OS细胞系的细胞增殖，而对正常细胞的细胞毒性相对较低。进一步证实ALT可能通过逆转上皮间质转化（EMT）过程和抑制基质金属蛋白酶（MMPs）而减少细胞迁移、侵袭。此外，我们证实，ALT促进人OS细胞的凋亡，并将细胞周期阻滞在G2/M期。此外，我们证实了ALT在体内异种移植模型中抑制OS 143细胞的肿瘤生长和转移。机制上，ALT抑制Wnt/β-catenin和p38、ERK 1/2和JNK丝裂原活化蛋白激酶（MAPK）信号通路的活性。值得注意的是，ALT和Wnt/β-连环蛋白抑制剂的组合以及ALT和MAPK抑制剂的组合导致对抑制OS细胞的增殖、迁移和侵袭的协同作用。结论ALT可能通过抑制Wnt/β-Catenin和MAPKs信号通路抑制人OS细胞增殖、转移和促进凋亡。
Although there are many therapeutic strategies such as surgery and chemotherapy, the prognosis of osteosarcoma (OS) is still far from being satisfactory. It is urgent to develop more effective, tolerable and safe drugs for the treatment of OS. In the present study, we investigated the anti-OS activity of Alantolactone (ALT), a natural eucalyptone sesquiterpene lactone mainly exists in Inula helenium, and probed the possible mechanism involved. We demonstrated that ALT significantly inhibited cell proliferation of various human OS cell lines while had relative lower cytotoxicity against normal cells. Then, we validated that ALT reduced migration, decreased invasion possibly through reversing epithelial mesenchymal transition (EMT) process and suppressing Matrix metalloproteinases (MMPs). Moreover, we confirmed that ALT promoted apoptosis and arrested cell cycle at G2/M phase of human OS cells in vitro. In addition, we confirmed that ALT restrained tumor growth and metastasis of OS 143 cells in a xenograft model in vivo. Mechanistically, ALT inhibited the activity of Wnt/β-catenin and p38, ERK1/2 and JNK Mitogen Activated Protein Kinases (MAPKs) signal pathway. Notably, the combination of ALT and Wnt/β-catenin inhibitor, as well as the combination of ALT and MAPKs inhibitors resulted in a synergistically effect on inhibiting the proliferation, migration and invasion of OS cells. Collectively, our results validate the ALT may inhibit proliferation, metastasis and promotes apoptosis of human OS cells possibly through suppressing Wnt/β-Catenin and MAPKs signaling pathways.
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