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Shikonin inhibits cancer cell cycling by targeting Cdc25s

文献类型： 外文期刊

作者： Zhang, Shoude 1 ; Gao, Qiang 1 ; Li, Wei 3 ; Zhu, Luwei 2 ; Shang, Qianhan 1 ; Feng, Shuo 1 ; Jia, Junmei 1 ; Jia, Qiangq 1 ;

作者机构： 1.Qinghai Univ, State Key Lab Plateau Ecol & Agr, 251 Ningda Rd, Xining 810016, Qinghai, Peoples R China

2.Qinghai Univ, Dept Pharm, Med Coll, 16 Kunlun Rd, Xining 810016, Qinghai, Peoples R China

3.Qinghai Acad Agr & Forestry Sci, 251 Ningda Rd, Xining 810016, Qinghai, Peoples R China

关键词： Shikonin; Cdc25s; Anticancer; Cell cycle progression

期刊名称：BMC CANCER （ 影响因子：4.43； 五年影响因子：4.372 ）

ISSN： 1471-2407

年卷期： 2019 年 19 卷

页码：

收录情况： SCI

摘要： BackgroundShikonin, a natural naphthoquinone, is abundant in Chinese herb medicine Zicao (purple gromwell) and has a wide range of biological activities, especially for cancer. Shikonin and its analogues have been reported to induce cell-cycle arrest, but target information is still unclear. We hypothesized that shikonin, with a structure similar to that of quinone-type compounds, which are inhibitors of cell division cycle 25 (Cdc25) phosphatases, will have similar effects on Cdc25s. To test this hypothesis, the effects of shikonin on Cdc25s and cell-cycle progression were determined in this paper.MethodsThe in vitro effects of shikonin and its analogues on Cdc25s were detected by fluorometric assay kit. The binding mode between shikonin and Cdc25B was modelled by molecular docking. The dephosphorylating level of cyclin-dependent kinase 1 (CDK1), a natural substrate of Cdc25B, was tested by Western blotting. The effect of shikonin on cell cycle progression was investigated by flow cytometry analysis. We also tested the anti-proliferation activity of shikonin on cancer cell lines by MTT assay. Moreover, in vivo anti-proliferation activity was tested in a mouse xenograft tumour model.ResultsShikonin and its analogues inhibited recombinant human Cdc25 A, B, and C phosphatase with IC50 values ranging from 2.140.21 to 13.45 +/- 1.45M irreversibly. The molecular modelling results showed that shikonin bound to the inhibitor binding pocket of Cdc25B with a favourable binding mode through hydrophobic interactions and hydrogen bonds. In addition, an accumulation of the tyrosine 15-phosphorylated form of CDK1 was induced by shikonin in a concentration-dependent manner in vitro and in vivo. We also confirmed that shikonin showed an anti-proliferation effect on three cancer cell lines with IC50 values ranging from 6.15 +/- 0.46 to 9.56 +/- 1.03M. Furthermore, shikonin showed a promising anti-proliferation effect on a K562 mouse xenograph tumour model.ConclusionIn this study, we provide evidence for how shikonin induces cell cycle arrest and functions as a Cdc25s inhibitor. It shows an anti-proliferation effect both in vitro and in vivo by mediating Cdc25s.

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