左旋棉酚通过下调X连锁凋亡抑制蛋白增强表柔比星抑制肝细胞癌的体外作用

蒋文斌; 孙梁博; 杜烨湘; 肖云华; 黎伯胜; 闫小晶; 吴亚冉; 连继勤; 何凤田

doi:10.16016/j.2097-0927.202201161

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左旋棉酚通过下调X连锁凋亡抑制蛋白增强表柔比星抑制肝细胞癌的体外作用

基础医学 | 更新时间：2026-01-09

- 左旋棉酚通过下调X连锁凋亡抑制蛋白增强表柔比星抑制肝细胞癌的体外作用
- (-)-Gossypol enhances epirubicin's anti-tumor effects on hepatocellular carcinoma in vitro via down-regulating X-linked inhibitor of apoptosis protein
- 陆军军医大学学报 2022年44卷第16期页码：1599-1605
- 作者机构：
  
  1.400038 重庆，陆军军医大学(第三军医大学)：基础医学院生物化学与分子生物学教研室
  2.400038 重庆，陆军军医大学(第三军医大学)：药学与检验医学系临床生物化学教研室
  3.400038 重庆，陆军军医大学(第三军医大学)：第一附属医院核医学科
- 作者简介：
  
  [何凤田，E-mail: hefengtian66@aliyun.comHE Fengtian, E-mail: hefengtian66@aliyun.com
- 基金信息：
  
  重庆市博士后自然科学基金项目(cstc2021jcyj-bshX0200);重庆市博士后特别资助项目(2021XM2050);国家自然科学基金面上项目(81872024)
- DOI：10.16016/j.2097-0927.202201161
  中图分类号： R735.7;R966;R979.1
- 收稿：2022-01-19，
  
  修回：2022-04-06，
  
  纸质出版：2022-08-30
- 稿件说明：
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蒋文斌, 孙梁博, 杜烨湘, 等. 左旋棉酚通过下调X连锁凋亡抑制蛋白增强表柔比星抑制肝细胞癌的体外作用[J]. 陆军军医大学学报, 2022,44(16):1599-1605.

Wenbin JIANG, Liangbo SUN, Yexiang DU, et al. (-)-Gossypol enhances epirubicin's anti-tumor effects on hepatocellular carcinoma in vitro via down-regulating X-linked inhibitor of apoptosis protein[J]. Journal of Army Medical University, 2022, 44(16): 1599-1605.
蒋文斌, 孙梁博, 杜烨湘, 等. 左旋棉酚通过下调X连锁凋亡抑制蛋白增强表柔比星抑制肝细胞癌的体外作用[J]. 陆军军医大学学报, 2022,44(16):1599-1605. DOI： 10.16016/j.2097-0927.202201161.

Wenbin JIANG, Liangbo SUN, Yexiang DU, et al. (-)-Gossypol enhances epirubicin's anti-tumor effects on hepatocellular carcinoma in vitro via down-regulating X-linked inhibitor of apoptosis protein[J]. Journal of Army Medical University, 2022, 44(16): 1599-1605. DOI： 10.16016/j.2097-0927.202201161.

摘要

目的

探讨左旋棉酚增强表柔比星杀伤肝细胞癌(hepatocellular carcinoma

HCC)细胞的作用及可能机制。

方法

将HCC细胞(Hep3B及HuH7)分为溶剂对照组、左旋棉酚处理组、表柔比星处理组、联合用药组、对照siRNA+表柔比星组、沉默X连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis protein

XIAP)+表柔比星处理组、对照质粒+联合用药组、过表达XIAP+联合用药组，采用CCK-8方法检测各组细胞存活情况；流式细胞术检测各组细胞凋亡情况；Western blot检测剪切型聚(腺苷二磷酸-核糖)聚合酶[cleaved poly (ADP-ribose) polymerase

Cle-PARP]水平、XIAP水平及真核起始因子4E (eukaryotic initiation factor 4E

eIF4E)磷酸化水平。

结果

与溶剂对照相比，低浓度的左旋棉酚(5 μmol/L)单独处理对HCC细胞存活无明显抑制作用(

0.05)，而将左旋棉酚与表柔比星联合使用后可显著增强表柔比星对HCC细胞的杀伤(

0.05)、促进HCC细胞的凋亡及对剪切型PARP的诱导，同时还能抑制表柔比星诱导的XIAP上调及eIF4E磷酸化。此外，表柔比星抑制HCC细胞存活及升高剪切型PARP的能力能被沉默XIAP所增强，而被过表达XIAP所抑制。

结论

左旋棉酚可增强表柔比星抑制HCC细胞存活促进细胞凋亡的能力，其机制可能与抑制XIAP上调和eIF4E磷酸化有关，提示左旋棉酚可作为表柔比星治疗HCC的潜在增敏剂。

Abstract

Objective

To investigate mechanism and effect on (-)-gossypol enhancing epirubicin killing hepatocellular carcinoma (HCC) cells.

Methods

HCC cells (Hep 3B and HuH7) were divided into 8 groups: control

(-)-gossypol

epirubicin

combination

si-control+epirubicin

si-X-linked inhibitor of apoptosis protein (XIAP)+ epirubicin

empty vector+ combination and pEBB-XIAP+ combination groups. Cell viability of each group was detected by CCK-8 assay; Cell apoptosis of each group was detected by flow cytometry and the level of cleavaged PARP

XIAP and eIF4E phosphorylation was detected by Western blot assay.

Results

Compared with the control group

no major effect was observed on cell viability exposed to (-)-gossypol in 5 μmol/L (

0.05). Combination of (-)-gossypol and epirubicin significantly enhanced the anti-survival effect on HCC cells (

0.05)

promoted cells apoptosis

increased the induction of cleavaged PARP

and inhibited XIAP up-regulation and eIF4E phosphorylation induced by epirubicin in HCC cells. Silencing XIAP promoted epirubicin to kill HCC cells and induced PARP cleavaged; Furthermore

XIAP over-expression attenuated epirubicin-induced anti-survival and pro-apoptosis of HCC cells enhanced by (-)-gossypol.

Conclusion

The combination of (-)-gossypol and epirubicin significantly inhibits HCC cells' survival and promotes cell apoptosis

via

suppressing epirubicin-induced phosphorylation of eIF4E and up-regulation of XIAP

suggesting that (-)-gossypol holds promise as a sensitizer for epirubicin-based HCC therapy.

关键词

Keywords

references

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