Antitumor activity of 2 new evodiamine derivatives against small-cell lung cancer cells <italic style="font-style: italic">in vitro</italic>

Xuejun JIANG; Jianbo YANG; Mei ZENG; Jingqing ZHANG; Xueyuan HU; Yingju LIU

doi:10.16016/j.1000-5404.201811186

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Antitumor activity of 2 new evodiamine derivatives against small-cell lung cancer cells in vitro

Basic Medicine | 更新时间：2026-01-09

- Antitumor activity of 2 new evodiamine derivatives against small-cell lung cancer cells in vitro
- Journal of Third Military Medical University Vol. 41, Issue 10, Pages: 961-968(2019)
- 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：
- 基金信息：
  
  Natural Science Foundation of Chongqing(CSTC2015zdcy-ztzx120003)
- DOI：10.16016/j.1000-5404.201811186
  CLC： R730.53;R734.2;R931.6
- Received：27 November 2018，
  
  Revised：2019-01-02，
  
  Published：30 May 2019
- 稿件说明：
移动端阅览
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：

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

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

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

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%(

END

=0.000

EAD

=0.046

24 h)、9.10%和43.37%(

END

=0.000

EAD

=0.000

48 h)、5.24%和29.55%(

END

=0.000

EAD

=0.000

72 h); 而EVO处理组存活率为60.81%(

=0.038

24 h)、21.99%(

=0.000

48 h)、18.51%(

=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%(

=0.000)和19.73%(

=0.029)

且分别有79.78%(

=0.001)和77.72%(

=0.001)的细胞被阻滞在G

/M期。END、EAD处理48 h后

与Control组相比

H1688细胞中Caspase 9(

END

=0.011

EAD

=0.026)、Caspase 12(

END

=0.031

EAD

=0.018)、Caspase 3(

END

=0.002

EAD

=0.043)、Cyt C(

END

=0.023

EAD

=0.028)等凋亡相关蛋白均上调。与EVO相比

END对Caspase 3(

=0.026)和Cyt C(

=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

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

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

Human SCLC cell line H1688 was treated with EVO

END

or EAD at different concentrations for 24

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

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% (

=0.000) and 61.20% (

=0.046) at 24 h

to 9.10% (

=0.000) and 43.37% (

=0.000) at 48 h

and to 5.24% (

=0.000) and 29.55% (

=0.000) at 72 h

respectively; the viability of EVO-treated cells was 60.81% (

=0.038) at 24 h

21.99% (

=0.000) at 48 h

and 18.51% (

=0.000) at 72 h. Treatments of the cells with 10 μmol/L END and EAD for 24

both induced obvious cell apoptosis with apoptotic rates of 54.98% (

=0.000) and 19.73% (

=0.029)

respectively

and caused cell cycle arrest in G

/M phase in 77.78% (

=0.001) and 77.72% (

=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(

=0.011

0.026)

Caspase-12(

=0.031

0.018)

Caspase-3(

=0.002

0.043) and Cyt C(

=0.023

0.028) in H1688 cells. END produced stronger effects than EVO in up-regulating caspase-3(

=0.026) and Cyt C(

=0.002); the effects of EAD on caspase family and Cyt C were similar to those of EVO.

Conclusion

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

/M phase and induce apoptosis of H1688 cells

via

the mitochondrial pathway.

关键词

Keywords

references

YANG F, SHI L, LIANG T, et al. Anti-tumor effect of evodiamine by inducing Akt-mediated apoptosis in hepatocellular carcinoma[J]. Biochem Biophys Res Commun, 2017, 485(1): 54-61. DOI: 10.1016/j.bbrc.2017.02.017.

WU W S, CHIEN CC, LIU K H, et al. Evodiamine prevents glioma growth, induces glioblastoma cell apoptosis and cell cycle arrest through JNK activation[J]. Am J Chin Med, 2017, 45(4): 879-899. DOI: 10.1142/S0192415X17500471.

ZHONG Z F, TAN W, WANG S P, et al. Anti-proliferative activity and cell cycle arrest induced by evodiamine on paclitaxel-sensitive and -resistant human ovarian cancer cells[J]. Sci Rep, 2015, 5: 16415. DOI: 10.1038/srep16415.

FANG C S, ZHANG J Q, QI D, et al. Evodiamine induces G2/M arrest and apoptosis via mitochondrial and endoplasmic reticulum pathways in H446 and H1688 human small-cell lung cancer cells[J]. PLoS ONE, 2014, 9(12): e115204. DOI: 10.1371/journal.pone.0115204.

祁迪, 谭群友, 王如文, 等.吴茱萸碱抑制PI3K/AKT通路诱导小细胞肺癌H1688和H446细胞凋亡[J].第三军医大学学报, 2016, 38(4): 330-337. DOI: 10.16016/j.1000-5404.201508031.

QI D, TAN Q Y, WANG R W, et al. Evodiamine induces apoptosis of small-cell lung cancer H1688 and H446 cells via inhibiting PI3K/AKT pathway[J]. J Third Mil Med Univ, 2016, 38(4): 330-337. DOI: 10.16016/j.1000-5404.201508031.

徐俊杰, 杨然, 杨芳景, 等.吴茱萸碱抗肿瘤机制的研究进展[J].上海交通大学学报(医学版), 2018, 38(5): 578-583. DOI: 10.3969/j.issn.1674-8115.2018.05.020.

XU J J, YANG R, YANG F J, et al. Recent advances in the antitumor effects of evodiamine[J]. J Shanghai Jiaotong Univ (Med Sci), 2018, 38(5) : 578-583. DOI: 10.3969/j.issn.1674-8115.2018.05.020

李娜.吴茱萸碱衍生物的合成及其药效学和药代动力学初步评价[D].重庆: 重庆医科大学, 2016.

LI N. The synthesis of evodiamine derivatives and preliminary evaluation of the pharmacodynamics and pharmacokinetics[D].Chongqing: Chongqing Medical University, 2016.

万坤.吴茱萸碱衍生物EVB的合成及其纳米粒的初步评价[D].重庆: 重庆医科大学, 2014. [http://cdmd.cnki.com.cn/Article/CDMD-10631-1015575856.htm .

WAN K. The synthesis of evodiamine derivative and preliminary evaluation of EVB loaded with nanoparticles[D]. Chongqing: Chongqing Medical University, 2014.

胡雪原, 李娜, 张景勍, 等.一种吴茱萸碱衍生物的制备方法:

CN201510725965.1[P]. 2015-12-23. HU X Y, LI N, ZHANG J Q, et al.The method for preparing a derivative of evodia officinalis: CN201510725965.1[P].2015-12-23.

姚迪, 孙晶晶, 刘雷, 等. LC-MS/MS法测定大鼠血浆中的吴茱萸碱、吴茱萸次碱和吴茱萸内酯及其生物利用度的研究[J].华西药学杂志, 2014, 29(3): 298-302. DOI: 10.13375/j.cnki.wcjps.2014.03.022.

YAO D, SUN J J, LIU L, et al. Simultaneous determination and absolute oral bioavailability of evodiamine, rutaecarpine and evodin concentration in the rat plasma by LC-MS/MS[J]. West China J Pharm Sci, 2014, 29(3): 298-302. DOI: 10.13375/j.cnki.wcjps.2014.03.022.

晏声蕾, 胡江波, 王薛, 等.吴茱萸碱油包水型复合纳米乳的药代动力学和在体肠吸收[J].第二军医大学学报, 2017, 38(2): 249-252. DOI: 10.16781/j.0258-879x.2017.02.0249.

YAN S L, HU J B, WANG X, et al. Pharmacokinetics and in situintestinal absorption of evodiamine complex water-in-oil nanoemulation[J]. Acad J Second Military Med Univ, 2017, 38(2): 249-252. DOI: 10.16781/j.0258-879x.2017.02.0249.

CHRISTODOULOU M S, SACCHETTI A, RONCHETTI V, et al. Quinazolinecarboline alkaloid evodiamine as scaffold for targeting topoisomerase Ⅰ and sirtuins[J]. Bioorg Med Chem, 2013, 21(22): 6920-6928. DOI: 10.1016/j.bmc.2013.09.030.

ZHAO N, TIAN K T, CHENG K G, et al. Antiproliferative activity and apoptosis inducing effects of nitric oxide donating derivatives of evodiamine[J]. Bioorg Med Chem, 2016, 24(13): 2971-2978. DOI: 10.1016/j.bmc.2016.05.001.

SONG S, CHEN Z, LI S, et al. Design, synthesis and evaluation of N13-substituted evodiamine derivatives against human cancer cell lines[J]. Molecules, 2013, 18(12): 15750-15768. DOI: 10.3390/molecules181215750.

CHEN T C, CHIEN CC, WU M S, et al. Evodiamine from Evodia rutaecarpa induces apoptosis via activation of JNK and PERK in human ovarian cancer cells[J]. Phytomedicine, 2016, 23(1): 68-78. DOI: 10.1016/j.phymed.2015.12.003.

WEI W, CHEN H, WANG Z, et al. Enhanced antitumor efficacy of gemcitabine by evodiamine on pancreatic cancer via regulating PI3K/Akt pathway[J]. Int J Biol Sci, 2012, 8(1): 1-14. DOI: 10.7150/ijbs.8.1.

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⁰

Antitumor activity of 2 new evodiamine derivatives against small-cell lung cancer cells in vitro

DOI：10.16016/j.1000-5404.201811186

摘要

Abstract

关键词

Keywords

references