Inhibitory Effects of Ligustrazine Plus Emodin on Expression of VEGF-related Factors in Ascites Carcinoma Walker-256 Cells

Ying-lan MAO; Mei ZHAO; Na HU; Jiao-yan YU; Wei JIANG

doi:10.13422/j.cnki.syfjx.20211893

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Inhibitory Effects of Ligustrazine Plus Emodin on Expression of VEGF-related Factors in Ascites Carcinoma Walker-256 Cells

更新时间：2021-09-07

- Inhibitory Effects of Ligustrazine Plus Emodin on Expression of VEGF-related Factors in Ascites Carcinoma Walker-256 Cells
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 27, Issue 19, Pages: 80-87(2021)
- 作者机构：
  
  空军军医大学第二附属医院，西安 710038
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20211893
  CLC： R22;R242;R285.5;R2-031;R979.1
- Received：06 April 2021，
  
  Published Online：31 August 2021，
  
  Published：05 October 2021
- 稿件说明：
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毛应岚,赵美,胡娜等.川芎嗪联合大黄素抑制腹水癌细胞HIF-1α通路相关因子表达的作用研究[J].中国实验方剂学杂志,2021,27(19):80-87.

MAO Ying-lan,ZHAO Mei,HU Na,et al.Inhibitory Effects of Ligustrazine Plus Emodin on Expression of VEGF-related Factors in Ascites Carcinoma Walker-256 Cells[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(19):80-87.
毛应岚,赵美,胡娜等.川芎嗪联合大黄素抑制腹水癌细胞HIF-1α通路相关因子表达的作用研究[J].中国实验方剂学杂志,2021,27(19):80-87. DOI： 10.13422/j.cnki.syfjx.20211893.

MAO Ying-lan,ZHAO Mei,HU Na,et al.Inhibitory Effects of Ligustrazine Plus Emodin on Expression of VEGF-related Factors in Ascites Carcinoma Walker-256 Cells[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(19):80-87. DOI： 10.13422/j.cnki.syfjx.20211893.

摘要

目的

从抑制癌细胞缺氧诱导因子（HIF）信号通路中核转录因子-

B（NF-

B），HIF-1

及血管内皮生长因子-C（VEGF-C）的角度探讨川芎嗪和大黄素合用抑制腹水癌细胞新生血管的作用。

方法

50只SD大鼠随机分为假手术组、模型组、川芎嗪组、大黄素组、川芎嗪+大黄素组，各实验组采用原位注射法对正常大鼠肝脏注射大鼠腹水癌细胞（Walker-256细胞），假手术组注射同等体积生理盐水，并分组灌胃给药川芎嗪（10 mg·kg

-1

），大黄素（10 mg·kg

-1

），川芎嗪+大黄素（川芎嗪10 mg·kg

-1

+大黄素10 mg·kg

-1

），给药7 d后取实验组肝脏肿瘤接种组织样本制作病理切片，观察肿瘤细胞存留状态和VEGF的表达情况。分别构建Walker-256细胞体外氧糖剥夺模型（缺氧缺糖模型）、单缺氧模型和单缺糖模型。川芎嗪组、大黄素组及川芎嗪+大黄素组均选择不影响Walker-256增殖的3个连续浓度作为考察浓度，造模前给药，模型处理时间4 h，检测各组细胞培养上清液中HIF-1

，VEGF-C，NF-

B的水平。

结果

大鼠肝脏在接种Walker-256细胞后，肝脏总质量明显升高（

0.05），川芎嗪组，大黄素组和川芎嗪+大黄素组肝脏总质量较模型组明显降低（

0.05），组织病理学检测显示，各给药组肝脏组织中的VEGF表达响应均低于模型组；在细胞水平，川芎嗪组和川芎嗪+大黄素组缺氧缺糖模型的HIF-1

，VEGF-C，NF-

B水平均明显降低（

0.05），呈一定的剂量依赖性，对单缺氧模型作用有一定降低作用；大黄素1×10

-2

，1×10

-3

mol·L

-1

组和川芎嗪+大黄素1×10

-2

，1×10

-3

mol·L

-1

组明显降低缺氧缺糖和单缺糖模型中HIF-1

，NF-

B的水平（

0.05），而所有给药组对单缺糖模型中VEGF-C作用不显著，差异无统计学意义。

结论

川芎嗪和大黄素单用和川芎嗪+大黄素联合使用均可抑制大鼠肝脏在接种Walker-256细胞后重量的异常升高，并抑制肝脏组织的VEGF表达；川芎嗪和大黄素可以抑制NF-

B，HIF-1

的蛋白表达，从而减少了HIF-1

转录激活的转移相关靶基因蛋白VEGF的表达、限制肿瘤细胞新生血管的生成以达到抑制腹水癌细胞侵袭和扩散。其中川芎嗪对缺氧的作用最显著，葡萄糖对川芎嗪的作用有干预，与大黄素合用时葡萄糖的干预作用降低，合用对肿瘤细胞的作用更稳定。

Abstract

Objective

To investigate the effects of ligustrazine combined with emodin on angiogenesis of ascites carcinoma Walker-256 cells by observing their inhibition against nuclear factor-

B （NF-

B）， hypoxia-inducible factor-1

（HIF-1

）， and vascular endothelial growth factor-C （VEGF-C） in HIF signaling pathway.

Method

Fifty SD rats were randomly divided into sham operation group， model group， ligustrazine group， emodin group and ligustrazine combined with emodin group. Following the in situ injection of rat ascites carcinoma Walker-256 cells into the liver of normal rats， they were grouped and administered with ligustrazine （10 mg·kg

-1

）， emodin （10 mg·kg

-1

）， and ligustrazine （10 mg·kg

-1

） plus emodin （10 mg·kg

-1

） for seven days. Afterwards， the tumor-inoculated liver tissue was sampled from the experimental group and prepared into pathological sections for investigating tumor cell survival and VEGF expression. The

in vitro

hypoxia and hypoglycemia model （oxygen-glucose deprivation model）， hypoxia model， and hypoglycemia model of Walker-256 cells were constructed respectively. In the ligustrazine group， emodin group， and ligustrazine combined with emodin group， three consecutive concentrations that did not affect the proliferation of Walker-256 cells were selected for investigation. The drugs were administered before modeling， and the model treatment lasted for 4 h. The levels of HIF-1

， VEGF-C， and NF-

B in the cell culture supernatant of each group were tested.

Result

After the rat liver was inoculated with Walker-256 cells， the total liver mass was significantly increased（

0.05）， higher than that in the ligustrazine group， the emodin group， or the ligustrazine combined with emodin group（

0.05）. Histopathological examination showed that the response of VEGF expression in the liver tissue of each administration group was lower than that of the model group. At the cellular level， the levels of HIF-1

， VEGF-C， and NF-

B in oxygen-glucose deprivation model of the ligustrazine group and the ligustrazine combined with emodin group were significantly reduced（

0.05）， exhibiting a certain dose-dependent response， followed by the reduction in the hypoxia model. The levels of HIF-1

and NF-

B in the oxygen-glucose deprivation model and the hypoglycemia model of the emodin（1×10

-2

，1×10

-3

mol·L

-1

） group and the ligustrazine combined with emodin（1×10

-2

，1×10

-3

mol·L

-1

） group were significantly reduced， but there was no significant change in VEGF-C level of the hypoxia model of all the administration groups.

Conclusion

Ligustrazine or emodin alone or their combination inhibits the abnormal increase in the weight of rat liver after inoculation with Walker-256 cells and the expression of VEGF in the liver tissue. Ligustrazine and emodin inhibit the protein expression of NF-

B and HIF-1

， thereby reducing the gene and protein expression of metastasis-related target VEGF-A activated by HIF-1

transcription， restricting tumor cell neovascularization， and inhibiting the invasion and spread of ascites carcinoma cells. Among them， ligustrazine has the most significant effect against hypoxia. Glucose interferes with the effect of ligustrazine. The combination of ligustrazine with emodin is conducive to diminishing the intervention of glucose and stabilizing the inhibition against tumor cells.

关键词

Keywords

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