SYUNZ-16, a newly synthesized alkannin derivative, induces tumor cells apoptosis and suppresses tumor growth through inhibition of PKB/AKT kinase activity and blockade of AKT/FOXO signal pathway
SYUNZ-16, a newly synthesized alkannin derivative, induces tumor cells apoptosis and suppresses tumor growth through inhibition of PKB/AKT kinase activity and blockade of AKT/FOXO signal pathway
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DOI：
10.1002/ijc.25032
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发表时间：
2010-07-01
影响因子：
6.4
通讯作者：
Zhu, Xiao-Feng
中科院分区：
文献类型：
--
作者：
Deng, Rong;Tang, Jun;Zhu, Xiao-Feng
紫草素是新疆紫草的主要活性成分，在中医药中被广泛应用。SYUNZ-16是紫草素的新衍生物。本研究以人肺腺癌细胞系GLC-82和人肝癌细胞系Hep 3B为研究对象，研究了SYUNZ-16对人肺腺癌细胞系GLC-82和人肝癌细胞系Hep 3B的体外抗癌作用。结果显示SYUNZ-16可通过诱导细胞凋亡抑制肿瘤细胞的增殖，AnnexinV阳性细胞数增加，caspase-3和PARP裂解增加。更重要的是，我们发现SYUNZ-16在无细胞体系中可以抑制AKT活性。用SYUNZ-16处理癌细胞降低了AKT的磷酸化。此外，SYUNZ-16以剂量依赖性和时间依赖性方式部分减弱FKHR和FKHRL 1的磷酸化水平，并导致外源性FKHR的核积聚增加，并上调癌细胞中Bim和TRADD的mRNA表达。进一步的研究表明，组成型激活的AKT 1转染可以减少SYUNZ-16介导的凋亡诱导。体内实验表明，SYUNZ-16对小鼠S-180肉瘤具有抑制作用。在GLC-82移植瘤模型中，SYUNZ-16 20 mg/kg/qod显著抑制肿瘤生长，TIC值为45.3%。SYUNZ-16可能是肿瘤细胞AKT信号通路的有效抑制剂。这些数据为SYUNZ-16作为潜在的抗肿瘤候选药物的进一步研究和开发提供了证据。
Alkannin is the major bioactive compound of Arnebia euchroma roots, which is used in many therapeutic remedies in Chinese traditional medicine. SYUNZ-16 is a new derivative of alkannin. In this study, anticancer effects of SYUNZ-16 on human lung adenocarcinoma cell line GLC-82 and human hepatocarcinoma cell line Hep3B were tested in vitro. The results showed SYUNZ-16 could obviously inhibit the proliferation of these cancer cell lines via induction of apoptosis, with the evidence of increasing AnnexinV-positive cells and cleaved caspase-3 and PARP fragments. More importantly, we found that SYUNZ-16 could inhibit AKT activity in cell-free system. Treatment of cancer cells with SYUNZ-16 decreased the phosphorylation of AKT. Additionally, SYUNZ-16 partially attenuated the phosphorylation levels of FKHR and FKHRL1 in a dose-dependent and time-dependent fashion, and led to an increase in the nuclear accumulation of exogenous FKHR, and upregulated the mRNA expression of Bim and TRADD in cancer cells. Further study showed that constitutively activated AKT1 transfection could reduce apoptosis induction mediated by SYUNZ-16. The in vivo experiments showed that SYUNZ-16 had inhibitory effects on S-180 sarcoma implanted to mice. And in GLC-82 xenograft models, SYUNZ-16 at 20 mg/kg/qod remarkably inhibited the tumor growth with the TIC value of 45.3%. Taken together, SYUNZ-16 might be a potent inhibitor of AKT signaling pathway in tumor cells. These data provide evidence for the development of SYUNZ-16 as a potential antitumor drug candidate for further research and development.