Paper - WANFANG MED ONLINE

You Position: Home > Paper

Glycogen Synthase Kinase Inhibitor (2'Z,3'E)-6-Bromo-indirubin3'-Oxime Enhances Drug Resistance to 5-FluorouracilChemotherapy in Colon Cancer Cells

( views:142, downloads:8 )

Author:: No author available

Journal Title:: Chinese Journal of Cancer Research

Issue:: 2

DOI:: 10.1007/sl1670-012-0116-9

Key Word:: Colorectal neoplasms;Drug resistance;Glycogen synthase kinase 3β;Fluorouracil;β-catenin;E2F-1

Abstract： Objective:To explore the effects and mechanism of glycogen synthase kinase 3β (GSK-3β3) 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 G2/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.

Reference

[1]YAN Li,Jing Li,Ming Lu,etc.Capecitabine Maintenance Therapy after First-Line Chemotherapy in Patients with Metastatic Colorectal Cancer[J].2010,(3).
[2]Forde JE,Dale TC.Glycogen synthase kinase 3: A key regulator of cellular fate[J].2007,64(15).
[3]S, Cascinu,C, Aschele,S, Barni,etc.Thymidylate synthase protein expression in advanced colon cancer: correlation with the site of metastasis and the clinical response to leucovorin-modulated bolus 5-fluorouracil.[J].1999,5.
[4]Ahmed FE.Molecular markers that predict response to colon cancer therapy.[J].2005,5(3).
[5]Suk-Bin, Seo,Jung-Gu, Hur,Mi-Ju, Kim,etc.TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3beta pathway and activation of caspases.[J].2010,9.
[6]Engel FB,Tseng AS,Keating MT.The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes[J].2006,13(9).
[7]Tesshi, Yamada,Yasuharu, Mori,Reiko, Hayashi,etc.Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice.[J].2003,63.
[8]Luo J.Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy.[J].2009,273(2).
[9]Patel PA.Evolution of 5-fluorouracil-based chemoradiation in the management of rectal cancer.[J].2011,22(4).
[10]Aligue R,Tauler A,Gil J,etc.Glycogen synthase kinase-3 beta binds to E2F1 and regulates its transcriptional activity[J].2007,1773(3).
[11]Nagano H,Takeda Y,Marubashi S,etc.Activation of Wnt/beta-catenin signalling pathway induces chemoresistance to interferon-alpha/5-fluorouracil combination therapy for hepatocellular carcinoma.[J].2009,100(10).
[12]Yong-Yu, Liu,Vineet, Gupta,Gauri A, Patwardhan,etc.Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and beta-catenin signaling.[J].2010,9.
[13]Weksler BB,Couraud PO,Barrand MA,etc.Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells.[J].2008,106(4).
[14]A, Leibovitz,J C, Stinson,W B, McCombs,etc.Classification of human colorectal adenocarcinoma cell lines.[J].1976,36.
[15]Johnson LF,Lester L,Dong S.Transcriptional control elements and complex initiation pattern of the TATA-less bidirectional human thymidylate synthase promoter.[J].2000,77(1).
[16]M, Kasahara,Y, Takahashi,T, Nagata,etc.Thymidylate synthase expression correlates closely with E2F1 expression in colon cancer.[J].2000,6.
[17]Guglielmi A,Puglisi F,Di Loreto C,etc.Lack of correlation between immunohistochemical expression of E2F-1, thymidylate synthase expression and clinical response to 5-fluorouracil in advanced colorectal cancer.[J].2004,15(1).
[18]Shih-Yi Chao,Jung-Hsien Chiang,A-Mei HuangWoan-Shan Chang.An integrative approach to identifying cancer chemoresistance-associated pathways[J].2011,4(1).
[19]Pataer A,Lu X,Yoshida K,etc.The Mitochondrial Apoptosis-Inducing Factor Plays a Role in E2F-1-Induced Apoptosis in Human Colon Cancer Cells.[J].2003,10(3).
[20]Pitchakarn, Pornsiri,Pompimon, Wilart,Ohnuma, Shinobu,etc.Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance[J].2012,23(1).
[21]Camins A,Yeste-Velasco M,Pallas M,etc.Glycogen synthase kinase-3 is involved in the regulation of the cell cycle in cerebellar granule cells.[J].2007,53(2).
[22]Glimelius Bengt,Magnusson Inger,Blomgren Henric,etc.Thymidylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy.[J].2002,20(7).
[23]Wijesuriya H,Hopkins S,Lim JC,etc.Decreased expression of multidrug efflux transporters in the brains of GSK-3beta transgenic mice.[J].2009,1276.
[24]Hariharan R,Phukan S,Babu VS,etc.GSK3beta: role in therapeutic landscape and development of modulators.[J].2010,160(1).
[25]Kurumi Y,Okumura K,Abe H,etc.Expression level of thymidylate synthase mRNA reflects 5-fluorouracil sensitivity with low dose and long duration in primary colorectal cancer.[J].2008,61(4).
[26]Dickey A,Thotala DK,Geng L.A new class of molecular targeted radioprotectors: GSK-3beta inhibitors.[J].2010,76(2).
[27]Diviya, Sinha,Zhiyong, Wang,Kathleen L, Ruchalski,etc.Lithium activates the Wnt and phosphatidylinositol 3-kinase Akt signaling pathways to promote cell survival in the absence of soluble survival factors.[J].2005,288(4).
[28]Tsuruo T,Hatano K,Matsuda K,etc.Relation between thymidylate synthase expression and survival in colon carcinoma, and determination of appropriate application of 5-fluorouracil by immunohistochemical method.[J].2000,7(3).
[29]Yuuki,Ougolkov A,Bilim V.Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma.[J].2009,101(12).
[30]Tanaka H,Nakamura M,Tanaka M,etc.Inhibition of Wnt signaling pathway decreases chemotherapy-resistant side-population colon cancer cells.[J].2010,30(6).
[31]Blivet Van Eggelpoel MJ,Beurel E,Cadoret A,etc.GSK-3beta reactivation with LY294002 sensitizes hepatoma cells to chemotherapy-induced apoptosis.[J].2005,27(1).
[32]Yao H,Wang M,Duan Z.Adrenaline induces chemoresistance in HT-29 colon adenocarcinoma cells.[J].2009,190(2).
[33]Makino T,Matsuura N,Yamasaki M,etc.Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma.[J].2011,104(4).
[34]Michael M. Gottesman,Joseph A. Ludwig,Jill K. Paterson,etc.Targeting multidrug resistance in cancer[J].2006,5(3).
[35]Shanmugam I,Terranova PF,Sun A,etc.Lithium suppresses cell proliferation by interrupting E2F-DNA interaction and subsequently reducing S-phase gene expression in prostate cancer.[J].2007,67(9).