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TDB-6对生存素及半胱天冬酶/Bcl-2/细胞色素C信号通路的调控诱导大肠癌细胞LoVo凋亡。

Regulation of survivin and caspase/Bcl-2/Cyto-C signaling by TDB-6 induces apoptosis of colorectal carcinoma LoVo cells.

作者信息

Shi Xianpeng, Wang Pengchong, Zhu Yaning, Li Li, Yang Tongfei, Sun Jingying, He Langchong, Zhou Nan, Zhang Peng

机构信息

Department of Pharmacy, Shaanxi Provincial People's Hospital, Xi'an, China.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.

出版信息

J Gastrointest Oncol. 2022 Oct;13(5):2322-2332. doi: 10.21037/jgo-22-780.

DOI:10.21037/jgo-22-780
PMID:36388656
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9660084/
Abstract

BACKGROUND

Colorectal carcinoma (CRC) treatment remains severe. Survivin is aberrantly overexpressed in CRC tissues and might be a potential target for CRC treatment. TDB-6 is a new taspine derivative. The purpose of this study is to investigate the inhibitory effect of TDB-6 on CRC and its underlying mechanism.

METHODS

The MTT assay and xenograft model were utilized to investigate the inhibitory effect of TDB-6 on LoVo cells and . Hoechst staining and Annexin-V FITC/PI analysis were conducted to study the effect of TDB-6 on LoVo cell apoptosis. Mitochondrial membrane potential (Δψm) assay was conducted to demonstrated whether TDB-6 could induce mitochondrial-mediated apoptosis of LoVo cells. Western blotting was conducted to investigate the effect of TDB-6 on survivin protein and caspase/Bcl-2/Cyto-C signaling.

RESULTS

The results indicated that TDB-6 induced mitochondria-mediated apoptosis and inhibited the proliferation and growth of LoVo cells and in . Mechanistic investigation utilizing western blotting indicated that TDB-6 inhibited survivin protein expression, and the inhibitory effect was augmented by TDB-6 and YM-155 co-administration, which revealed that TDB-6 might induce apoptosis of LoVo cells by targeted regulation of survivin. TDB-6 also regulated survivin downstream signaling. It significantly increased the protein level of cleaved caspase-3, cleaved caspase-7, cleaved caspase-9, cleaved-PARP, and Cyto-C, and decreased the protein level of Bcl-2.

CONCLUSIONS

TDB-6 might be a promising survivin inhibitor with great potential for CRC treatment.

摘要

背景

结直肠癌（CRC）的治疗仍然严峻。生存素在CRC组织中异常过表达，可能是CRC治疗的一个潜在靶点。TDB-6是一种新的唐松草碱衍生物。本研究的目的是探讨TDB-6对CRC的抑制作用及其潜在机制。

方法

采用MTT法和异种移植模型研究TDB-6对LoVo细胞的抑制作用。进行Hoechst染色和Annexin-V FITC/PI分析以研究TDB-6对LoVo细胞凋亡的影响。进行线粒体膜电位（Δψm）测定以证明TDB-6是否能诱导LoVo细胞的线粒体介导的凋亡。进行蛋白质印迹法以研究TDB-6对生存素蛋白和半胱天冬酶/Bcl-2/Cyto-C信号传导的影响。

结果

结果表明，TDB-6诱导线粒体介导的凋亡，并抑制LoVo细胞的增殖和生长。利用蛋白质印迹法进行的机制研究表明，TDB-6抑制生存素蛋白表达，并且TDB-6与YM-155联合给药增强了抑制作用，这表明TDB-6可能通过靶向调节生存素来诱导LoVo细胞凋亡。TDB-6还调节生存素下游信号传导。它显著增加了裂解的半胱天冬酶-3、裂解的半胱天冬酶-7、裂解的半胱天冬酶-9、裂解的PARP和Cyto-C的蛋白水平，并降低了Bcl-2的蛋白水平。

结论

TDB-6可能是一种有前途的生存素抑制剂，在CRC治疗中具有巨大潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/97a8ce6870d9/jgo-13-05-2322-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/8d80c47c027b/jgo-13-05-2322-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/5d33a33a14ae/jgo-13-05-2322-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/fa13e86ff892/jgo-13-05-2322-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/c448d75b9f60/jgo-13-05-2322-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/193a536e0608/jgo-13-05-2322-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/814f97311707/jgo-13-05-2322-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/97a8ce6870d9/jgo-13-05-2322-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/8d80c47c027b/jgo-13-05-2322-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/5d33a33a14ae/jgo-13-05-2322-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/fa13e86ff892/jgo-13-05-2322-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/c448d75b9f60/jgo-13-05-2322-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/193a536e0608/jgo-13-05-2322-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/814f97311707/jgo-13-05-2322-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/96be/9660084/97a8ce6870d9/jgo-13-05-2322-f7.jpg

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