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新型吴茱萸碱衍生物抗小细胞肺癌活性效应的初步评价
Antitumor activity of 2 new evodiamine derivatives against small-cell lung cancer cells
in vitro - 第三军医大学学报 2019年41卷第10期 页码：961-968
- 作者机构：
1.400016 重庆，重庆医科大学药学院：重庆市生物化学与分子药理学重点实验室
2.重庆市高校药物工程中心
- 作者简介：
[ 刘颖菊，E-mail:2553407160@qq.com LIU Yingju, E-mail:2553407160@qq.com
- 基金信息：重庆市自然科学基金(CSTC2015zdcy-ztzx120003)
DOI：10.16016/j.1000-5404.201811186
中图分类号： R730.53;R734.2;R931.6收稿：2018-11-27，
修回：2019-01-02，
纸质出版：2019-05-30
- 稿件说明：
移动端阅览
江雪均, 杨建波, 曾梅, 等. 新型吴茱萸碱衍生物抗小细胞肺癌活性效应的初步评价[J]. 第三军医大学学报, 2019,41(10):961-968.
Xuejun JIANG, Jianbo YANG, Mei ZENG, et al. Antitumor activity of 2 new evodiamine derivatives against small-cell lung cancer cells
in vitro [J]. Journal of Third Military Medical University, 2019, 41(10): 961-968.江雪均, 杨建波, 曾梅, 等. 新型吴茱萸碱衍生物抗小细胞肺癌活性效应的初步评价[J]. 第三军医大学学报, 2019,41(10):961-968. DOI： 10.16016/j.1000-5404.201811186.
Xuejun JIANG, Jianbo YANG, Mei ZENG, et al. Antitumor activity of 2 new evodiamine derivatives against small-cell lung cancer cells
in vitro [J]. Journal of Third Military Medical University, 2019, 41(10): 961-968. DOI： 10.16016/j.1000-5404.201811186.
摘要
目的
2
研究吴茱萸碱(evodiamine
EVO)的两种衍生物:硝基吴茱萸碱衍生物(10-nitro evodiamine derivatives
END)与氨基吴茱萸碱衍生物(10-amino evodiamine derivatives
EAD)对小细胞肺癌细胞株H1688的抗癌活性及机制。
方法
2
H1688细胞分别用不同浓度的吴茱萸碱EVO、END、EAD处理24、48、72 h后用MTT法检测其存活率; 10 μmol/L的EVO、END、EAD处理H1688细胞24 h后
流式细胞术检测其凋亡与周期; 同样浓度处理48 h后提取总蛋白
Western blot检测Caspase 12、Caspase 9、Caspase 3、细胞色素C(cytochome C
Cyt C)的表达。
结果
2
MTT结果显示
0.625μmol/L的END或EAD处理24 h后
即可观察到药物对H1688的抑制作用
20 μmol/L EVO、END和EAD处理24、48、72 h后
与0 μmol/L组存活率相比显著降低。END和EAD处理组H1688存活率分别为16.45%和61.20%(
P
END
=0.000
P
EAD
=0.046
24 h)、9.10%和43.37%(
P
END
=0.000
P
EAD
=0.000
48 h)、5.24%和29.55%(
P
END
=0.000
P
EAD
=0.000
72 h); 而EVO处理组存活率为60.81%(
P
=0.038
24 h)、21.99%(
P
=0.000
48 h)、18.51%(
P
=0.000
72 h)
其中20 μmol/L END对H1688抑制效果最好。10 μmol/L的END、EAD处理H1688 24 h后
细胞凋亡率明显升高
凋亡率分别为54.98%(
P
=0.000)和19.73%(
P
=0.029)
且分别有79.78%(
P
=0.001)和77.72%(
P
=0.001)的细胞被阻滞在G
2
/M期。END、EAD处理48 h后
与Control组相比
H1688细胞中Caspase 9(
P
END
=0.011
P
EAD
=0.026)、Caspase 12(
P
END
=0.031
P
EAD
=0.018)、Caspase 3(
P
END
=0.002
P
EAD
=0.043)、Cyt C(
P
END
=0.023
P
EAD
=0.028)等凋亡相关蛋白均上调。与EVO相比
END对Caspase 3(
P
=0.026)和Cyt C(
P
=0.002)作用都明显强于EVO
而EAD对Caspase家族与Cyt C的作用则与EVO类似。
结论
2
EVO的两种衍生物END、EAD都对小细胞肺癌细胞株H1688有体外抗肿瘤作用
这种作用呈时间、浓度依赖性
END体外抗肿瘤效果更好。
Abstract
Objective
2
To investigate the antitumor activity and the underlying mechanisms of 2 new derivatives of evodiamine (EVO)
namely nitro evodiamine derivatives (END) and amino evodiamine derivatives (EAD)
in cultured small-cell lung cancer (SCLC) cells.
Methods
2
Human SCLC cell line H1688 was treated with EVO
END
or EAD at different concentrations for 24
48
or 72 h
and the changes in the cell viability were assessed using MTT assay. The effects of treatment with 10 μmol/L EVO
END or EAD for 24 h on cell apoptosis and cell cycle were investigated using flow cytometry. Western blotting was performed to detect the changes in the expressions of Caspase-9
Caspase-12
Caspase-3
and cytochrome C (Cyt C) in the cells following treatment with 10 μmol/L EVO
END or EAD for 48 h.
Results
2
MTT assay showed that treatment with END or EAD for 24 h at the concentration as low as 0.625 μmol/L was sufficient to reduce the viability of H1688 cells. Treatment of the cells with 20 μmol/L END or EAD significantly lowered the cell viability to 16.45% (
P
=0.000) and 61.20% (
P
=0.046) at 24 h
to 9.10% (
P
=0.000) and 43.37% (
P
=0.000) at 48 h
and to 5.24% (
P
=0.000) and 29.55% (
P
=0.000) at 72 h
respectively; the viability of EVO-treated cells was 60.81% (
P
=0.038) at 24 h
21.99% (
P
=0.000) at 48 h
and 18.51% (
P
=0.000) at 72 h. Treatments of the cells with 10 μmol/L END and EAD for 24
h
both induced obvious cell apoptosis with apoptotic rates of 54.98% (
P
=0.000) and 19.73% (
P
=0.029)
respectively
and caused cell cycle arrest in G
2
/M phase in 77.78% (
P
=0.001) and 77.72% (
P
=0.001) of the cells
respectively. Treatments with 10 μmol/L END and EAD for 48 h both significantly upregulated the expression of Caspase-9(
P
=0.011
0.026)
Caspase-12(
P
=0.031
0.018)
Caspase-3(
P
=0.002
0.043) and Cyt C(
P
=0.023
0.028) in H1688 cells. END produced stronger effects than EVO in up-regulating caspase-3(
P
=0.026) and Cyt C(
P
=0.002); the effects of EAD on caspase family and Cyt C were similar to those of EVO.
Conclusion
2
Both of the two derivatives of EVO
END and EAD
and particularly the former
have concentration- and time-dependent antitumor effects against H1688 cells
in vitro
. Both END and EAD can cause cell cycle arrest in G
2
/M phase and induce apoptosis of H1688 cells
via
the mitochondrial pathway.
关键词
Keywords
references
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