Sulfasalazine antagonizes boosted metastasis of breast cancer induced by ionizing radiation

Ge HE; Guojian WANG; Na ZHAO; Shuang LONG; Tao WANG; Jia MING

doi:10.16016/j.2097-0927.202204064

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Sulfasalazine antagonizes boosted metastasis of breast cancer induced by ionizing radiation

Basic Medicine | 更新时间：2026-01-09

- Sulfasalazine antagonizes boosted metastasis of breast cancer induced by ionizing radiation
- Journal of Army Medical University Vol. 44, Issue 18, Pages: 1797-1808(2022)
- 作者机构：
  
  1.400010 重庆，重庆医科大学附属第二医院乳甲外科
  2.400038 重庆，陆军军医大学(第三军医大学)军事预防医学系防原医学教研室，全军复合伤研究所，创伤、烧伤与复合伤国家重点实验室，重庆市纳米医学工程研究中心
- 作者简介：
- 基金信息：
  
  the "Kuanren Elite" Backbone Talent Project of the Second Affiliated Hospital of Chongqing Medical University(KY2019G016);the Appropriate Health Technology Promotion Project of Chongqing Health Commission(2021jstg022)
- DOI：10.16016/j.2097-0927.202204064
  CLC： R737.9;R966;R979.1
- Received：10 April 2022，
  
  Revised：2022-05-05，
  
  Published：30 September 2022
- 稿件说明：
移动端阅览
Ge HE, Guojian WANG, Na ZHAO, et al. Sulfasalazine antagonizes boosted metastasis of breast cancer induced by ionizing radiation[J]. Journal of Army Medical University, 2022, 44(18): 1797-1808.
DOI：

Ge HE, Guojian WANG, Na ZHAO, et al. Sulfasalazine antagonizes boosted metastasis of breast cancer induced by ionizing radiation[J]. Journal of Army Medical University, 2022, 44(18): 1797-1808. DOI： 10.16016/j.2097-0927.202204064.

摘要

目的

评价柳氮磺吡啶(sulfasalazine，SSZ)对电离辐射(ionizing radiation，IR)诱导离体乳腺癌细胞上皮-间质转化(epithelial-to-mesenchymal transition

EMT)、迁移、侵袭等转移相关表型的抑制作用，探讨其作为治疗措施对在体局部IR促进乳腺癌肺转移的拮抗作用。

方法

以体外培养两种乳腺癌细胞株(MCF-7、4T1)为研究对象，采用不同剂量(2、4、6、8、10 Gy)X射线照射后观察细胞形态改变，Western blot检测Vimentin、Snail等EMT相关标志物的表达变化。选取4 Gy X射线照射细胞，评价SSZ(0.5 mmol/L)对IR后细胞EMT、迁移、侵袭等转移相关表型的影响，并检测MMP2/9和xCT等蛋白的表达。在BALB/c雌鼠建立4T1细胞乳腺癌肺转移模型，实验分4组：Con组、SSZ组、IR组和IR+SSZ组。IR采用局部X射线(4 Gy)照射；SSZ采用腹腔给药8 mg/只，2次/d；IR+SSZ组采用局部X射线(4 Gy)照射后，以腹腔给药SSZ 8 mg/只，2次/d。荷瘤30 d后取材，计算原位瘤大小和肺转移结节数目，HE染色观察原位瘤和肺转移灶情况。

结果

体外培养乳腺癌细胞在IR后出现明显的EMT形态改变，Vimentin、Snail等EMT相关蛋白表达上调，呈一定剂量相关性。SSZ能够抑制IR诱导的乳腺癌细胞EMT形态和标志蛋白改变，抑制IR诱导的乳腺癌细胞迁移和侵袭能力增强的表型(

0.05)，下调IR诱导的MMP2/9、xCT等蛋白增强表达。在体动物模型与离体细胞结果相对应，IR可以显著抑制原位瘤生长，与Con组比较，IR组[(1.24±0.32)cm

]

和IR+SSZ组[(0.83±0.54)cm

]

的小鼠原位瘤平均体积显著降低(

0.05)，且IR+SSZ组较IR组降低更显著(

0.05)；IR组小鼠肺转移结节数为[(19.00±8.31)个

]

，较Con组[(8.67±7.88)个

]

显著增多(

0.05)，IR+SSZ组小鼠肺转移结节数[(6.10±7.78)个

]

较IR组显著降低(

0.05)，而单纯SSZ组小鼠肺转移结节数[(4.30±5.39)个

]

与Con组相比差异无统计学意义。HE染色结果显示，IR组肺转移灶数量增多，面积增加，边界欠清，有明显弥散的趋势；而IR+SSZ组肺转移灶面积较小，边界较清晰。

结论

SSZ能有效抑制IR诱导乳腺癌细胞EMT、迁移、侵袭，并显著拮抗在体局部照射对乳腺癌肺转移的促进作用。

Abstract

Objective

To evaluate the inhibitory effects of sulfasalazine (SSZ) on ionizing radiation (IR) induced epithelial-to-mesenchymal transition (EMT)

migration

invasion

and other metastasis-related phenotypes in breast cancer cells

in vitro

and to investigate its antagonistic effects as a therapeutic measure against breast cancer lung metastasis promoted by

in vivo

local IR.

Methods

Cultured breast cancer cell lines MCF-7 and 4T1 were used to study the morphological change

s of cells after different doses of X-ray irradiation (2

8 and 10 Gy) and the expression changes of EMT-related markers such as Vimentin and Snail were detected by Western blotting. A cell model with 4 Gy of X-ray irradiation was selected to evaluate the effect of SSZ (0.5 mmol/L) on metastasis-related phenotypes such as EMT

migration

and invasion of cells after IR

and on the protein expression of MMP2/9 and xCT after IR. After xenograft model of 4T1 cell breast cancer lung metastasis was established in BALB/c female mice

the mice were divided into control group

SSZ group (intraperitoneal injection of 8 mg SSZ

2 times per day)

IR group (X-ray 4 Gy irradiation) and IR+SSZ group (X-ray 4 Gy irradiation

intraperitoneal injection of 8 mg SSZ

2 times per day). The tumor masses were harvested in 30 d after tumor loading

and the size of

in situ

tumor and the number of lung metastatic nodes were measured and calculated

and HE staining was used to observed

in situ

tumor and lung metastases.

Results

Cultured breast cancer cells showed significant EMT morphological alterations after IR

and the expression of Vimentin and Snail was upregulated in a dose-related manner. SSZ inhibited IR-induced changes in EMT morphology and marker proteins

suppressed IR-induced phenotypes of enhanced migration and invasion of breast cancer cells (

0.05)

and down-regulated IR-induced enhanced expression of MMP2/9

xCT

and other proteins.

In vivo

animal model corresponded to the

ex vivo

cellular results that IR significantly inhibited

in situ

tumor growth. Compared with the control mice (1.70±0.54 cm

)

the mean tumor volume was significantly smaller in the IR group (1.24±0.32 cm

) and IR+SSZ group (0.83± 0.54 cm

) (

0.05)

and the reduction was more significant in the latter than in the former group (

0.05).

The number of lung metastases in the IR group (19.00±8.31) was significantly higher than that in the Con group (8.67±7.88) (

0.05)

and the number in the IR+SSZ group (6.10±7.78) was significantly lower than the IR group (

0.05)

while the number in the SSZ group (4.30±5.39) was not statistically different from the Con group. HE pathology showed that the number of metastases in the IR group was increased

the area was enlarged

the border was not clear

and the metastases had a tendency to diffuse. In contrast

the lung metastases in the IR+SSZ group had clearer borders and a weaker tendency to invade outward.

Conclusion

SSZ effectively inhibits IR-induced EMT

migration

and invasion of breast cancer cells and significantly antagonizes the lung metastasis-promoting effects of

in vivo

local irradiation of breast cancer.

关键词

Keywords

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