LY294002 potentiates the anti-cancer effect of oxaliplatin for gastric cancer via death receptor pathway

AIM：To examine the effects of combined treatment of oxaliplatin and phosphatidylinositol 3’-kinase inhibitor,2-（4-morpholinyl） -8-phenyl-4H-1-benzopyran-4-one（LY294002） for gastric cancer. METHODS：Cell viability was evaluated by 3-（4,5-dimethylthiazol-2-yl） -2,5-diphenyltetrazolium bromide assay.Apo...

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Bibliographic Details
Published in:World journal of gastroenterology : WJG 2011-01, Vol.17 (2), p.181-190
Main Authors: Liu, Jie, Fu, Xue-Qiong, Zhou, Wei, Yu, Hong-Gang, Yu, Jie-Ping, Luo, He-Sheng
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Apoptosis
caspase
Caspases - metabolism
Cell Line, Tumor
Chromones - administration & dosage
Enzyme Inhibitors - administration & dosage
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Mice, Inbred BALB C
Morpholines - administration & dosage
Neoplasm Transplantation
Organoplatinum Compounds - administration & dosage
Original
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Receptors, Death Domain - metabolism
Stomach Neoplasms - drug therapy
Tetrazolium Salts - pharmacology
Thiazoles - pharmacology
Transfection
奥沙利铂
抗癌作用
死亡受体
流式细胞仪分析
生长抑制剂
细胞存活率
胃癌
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Summary:AIM：To examine the effects of combined treatment of oxaliplatin and phosphatidylinositol 3’-kinase inhibitor,2-（4-morpholinyl） -8-phenyl-4H-1-benzopyran-4-one（LY294002） for gastric cancer. METHODS：Cell viability was evaluated by 3-（4,5-dimethylthiazol-2-yl） -2,5-diphenyltetrazolium bromide assay.Apoptotic cells were detected by flow cytometric analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay.Western blotting and immuno-precipitation were used to examine protein expression and recruitment,respectively.Nuclear factorκB（NFκB） binding activities were investigated using electrophoretic mobility shift assay.Nude mice were used to investigate tumor growth. RESULTS：Treatment with combined oxaliplatin and LY294002 resulted in increased cell growth inhibi-tion and cell apoptosis in vitro,and increased tumor growth inhibition and cell death in the tumor mass in vivo.In MKN45 and AGS cells,oxaliplatin treatment promoted both protein kinase B（Akt） and NFκB activation,while pretreatment with LY294002 significantly attenuated oxaliplatin-induced Akt activity and NFκB binding.LY294002 promoted oxaliplatin-induced Fas ligand（FasL） expression,Fas-associated death domain protein recruitment,caspase-8,Bid,and caspase-3 activation,and the short form of cellular caspase-8/FLICEinhibitory protein（c-FLIPS） inhibition.In vivo,LY294002 inhibited oxaliplatin-induced activation of Akt and NFκB,and increased oxaliplatin-induced expression of FasL,inhibition of c-FLIPS,and activation of caspase-8,Bid,and caspase-3. CONCLUSION：Combination of oxaliplatin and LY294002 was therapeutically promising for gastric cancer treatment.The enhanced sensitivity of the combined treatment was associated with the activation of the death receptor pathway.
ISSN:1007-9327
2219-2840
DOI:10.3748/wjg.v17.i2.181