Trilobolide-6-O-isobutyrate suppresses hepatocellular carcinoma tumorigenesis through inhibition of IL-6/STAT3 signaling pathway
Trilobolide-6-O-isobutyrate suppresses hepatocellular carcinoma tumorigenesis through inhibition of IL-6/STAT3 signaling pathway
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Trilobolide-6-O-isobutyrate 通过抑制 IL-6/STAT3 信号通路抑制肝细胞癌肿瘤发生
DOI：
10.1002/ptr.7233
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发表时间：
2021
影响因子：
7.2
通讯作者：
Shen Dong-Yan
中科院分区：
文献类型：
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作者：
Zhou Xiu-Qiao;Mao Xiao-Mei;Fan Rui;Li Si-Yang;Shang Jin;Zhang Tong;Li Rui-Han;Li Hui-Qi;Hui Yang;Chen Wen-Hao;Wang Zhan-Xiang;Shen Dong-Yan
肝细胞癌（HCC）的发病率和死亡率都很高，但目前的治疗方法效果不佳，且副作用严重，因此必须探索新的、更有效的抗癌分子。中草药具有显著的抗肿瘤作用，被应用于临床肿瘤治疗的补充。在这里，我们报道了一种从三裂叶婆婆纳花中分离出的化合物三裂叶婆婆纳-6-O-异丁酸酯（TBB），对肝癌细胞具有显着的细胞毒性作用。我们发现TBB在体外时间和剂量依赖性地抑制HCC细胞的生长和集落形成。此外，TBB诱导细胞周期停滞在G2/M期，线粒体caspase依赖性凋亡，并抑制迁移和侵袭，以及糖酵解的HCC细胞。从机制上讲，我们的数据表明，TBB通过直接与STAT 3蛋白的TYR 640/657位点相互作用并降低p-STAT 3的水平来抑制STAT 3通路的激活。TBB还通过抑制IL-6/STAT 3信号通路调节PCNA、Ki 67、Cyclin B1、Cyclin E、Bax、Bcl 2、MMP 2/9和PGK 1的表达。最后，我们证实了TBB有效地消除了异种移植肿瘤模型中的肿瘤生长，而不会对健康组织造成明显的毒性。TBB的抗肿瘤活性及其作用机制的研究表明，TBB是一种很有前途的肝癌化疗药物。
Currently available therapies for hepatocellular carcinoma (HCC), with a high morbidity and high mortality, are only marginally effective and with sharp adverse side effects, which makes it compulsory to explore novel and more effective anticancer molecules. Chinese medicinal herbs exhibited prominent anticancer effects and were applied to supplement clinical cancer treatment. Here, we reported a compound, trilobolide‐6‐O‐isobutyrate (TBB), isolated from the flowers ofWedelia trilobatawith a markedly cytotoxic effect on HCC cells. We found that TBB time‐ and dose‐dependently inhibited HCC cells' growth and colony formation in vitro. Moreover, TBB induced cell cycle arrest at the G2/M phase, mitochondrial caspase‐dependent apoptosis, and suppressed migration and invasion, as well as the glycolysis of HCC cells. Mechanistically, our data indicated that TBB inhibited the STAT3 pathway activation by directly interacting with the TYR 640/657 sites of the STAT3 protein and decreasing the level of p‐STAT3. TBB also regulated the expression of PCNA, Ki67, Cyclin B1, Cyclin E, Bax, Bcl2, MMP2/9, and PGK1 through the inhibition of the IL‐6/STAT3 signaling pathway. Lastly, we confirmed that TBB effectively eliminated tumor growth without causing overt toxicity to healthy tissues in the xenograft tumor model. The exploration of anticancer activity and the underlying mechanism of TBB suggested its usage as a promising chemotherapeutic agent for HCC.