糖原合酶激酶 3β 抑制剂（2'Z,3'E）-6-溴靛红-3'-肟增强结肠癌细胞对 5-氟尿嘧啶化疗的耐药性。

Glycogen Synthase Kinase 3β Inhibitor (2'Z,3'E)-6-Bromo-indirubin- 3'-Oxime Enhances Drug Resistance to 5-Fluorouracil Chemotherapy in Colon Cancer Cells.

机构信息

Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; Department of Pathology, Qingyuan Hospital, Medical College, Jinan University, Qingyuan 511518, China.

出版信息

Chin J Cancer Res. 2012 Jun;24(2):116-23. doi: 10.1007/s11670-012-0116-9.

DOI:10.1007/s11670-012-0116-9

PMID:23359767

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3555271/

Abstract

OBJECTIVE

To explore the effects and mechanism of glycogen synthase kinase 3β (GSK-3β) inhibitor (2'Z,3'E)-6-bromo-indirubin-3'-oxime (BIO) on drug resistance in colon cancer cells.

METHODS

The colon cancer SW480 and SW620 cells were treated with BIO, 5-fluorouracil (5-FU) and BIO/5-FU, separately. Cell cycle distribution, apoptosis level and efflux ability of rhodamine 123 (Rh123) were detected by flow cytometry. The protein expressions of P-glycoprotein (P-gp), multidrug resistance protein 2 (MRP2), thymidylate synthase (TS), β-catenin, E2F-1 and Bcl-2 were detected by Western blot. β-catenin and P-gp were stained with double immunofluorescence and observed under a confocal microscope.

RESULTS

BIO up-regulated β-catenin, P-gp, MRP2 and TS, enhanced the efflux ability of Rh123, decreased Bcl-2 protein and gave the opposite effect to E2F-1 protein in SW480 and SW620 cells. Furthermore, BIO significantly inhibited cell apoptosis, increased S and G(2)/M phase cells, and reduced the cell apoptosis induced by 5-FU in SW480 cells, whereas the effects were slight or not obvious in SW620 cells.

CONCLUSION

GSK-3β was involved in drug resistance regulation, and activation of β-catenin and inhibition of E2F-1 may be the most responsible for the enhancement of 5-FU chemotherapy resistance induced by GSK-3β inhibitor BIO in colon cancer.

摘要

目的

探讨糖原合成酶激酶 3β（GSK-3β）抑制剂（2'Z，3'E）-6-溴靛红-3'-肟（BIO）对结肠癌耐药的影响及机制。

方法

分别用 BIO、5-氟尿嘧啶（5-FU）和 BIO/5-FU 处理结肠癌 SW480 和 SW620 细胞。采用流式细胞术检测细胞周期分布、凋亡水平和罗丹明 123（Rh123）外排能力。采用 Western blot 检测 P-糖蛋白（P-gp）、多药耐药相关蛋白 2（MRP2）、胸苷酸合成酶（TS）、β-连环蛋白、E2F-1 和 Bcl-2 的蛋白表达。采用双免疫荧光染色β-连环蛋白和 P-gp，并用共聚焦显微镜观察。

结果

BIO 上调了 SW480 和 SW620 细胞中的β-连环蛋白、P-gp、MRP2 和 TS，增强了 Rh123 的外排能力，降低了 Bcl-2 蛋白，对 E2F-1 蛋白产生相反的作用。此外，BIO 显著抑制了 SW480 细胞的细胞凋亡，增加了 S 和 G(2)/M 期细胞，减少了 5-FU 诱导的细胞凋亡，而在 SW620 细胞中的作用轻微或不明显。