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標題Title: Combretastatin A4-induced differential cytotoxicity and reduced metastatic ability by inhibition of AKT function in human gastric cancer cells
作者Authors: 溫義輝,Lin HL..等
上傳單位Department: 生物科技系
上傳時間Date: 2009-11-20
上傳者Author: 溫義輝
審核單位Department: 生物科技系
審核老師Teacher: 溫義輝
檔案類型Categories: 論文Thesis
關鍵詞Keyword: Combretastatin A4, AKT, gastric cancer cells
摘要Abstract: Combretastatin A4 (CA4) is a drug that targets tumor vasculature
to inhibit angiogenesis. Whether CA4 has a direct effect on
gastric cancer is not known. We herein investigated the effect
of CA4 on growth and metastasis of gastric cancer cells at
clinically achievable concentration and explored the associated
antitumor mechanisms. Nine human gastric cancer cell lines,
including two metastatic gastric cancer cell lines (AGS-GFPM1/
2), constitutively expressing green fluorescence protein (GFP)
were used. These metastatic AGS-GFPM1/2 cells expressed a
higher level of phosphorylated serine 473 on AKT (p-AKT). Our
results showed that CA4 (0.02–20 M) has significant in vitro
effects on reducing cell attachment, migration, invasiveness, as
well as cell cycle G2/M disturbance on p-AKT-positive gastric
cancer cells. In addition, a phosphoinositide 3-kinase inhibitor,
LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one
hydrochloride], a specific AKT inhibitor, and 0.2 to 20 M CA4
displayed a similar response profile on p-AKT-positive cells, suggesting
that CA4-induced effect was mediated by inhibition of the
PI3 kinase/AKT pathway. The results from in vivo GFP monitoring
system indicated that CA4 phosphate (CA4-P; 200 mg/kg) significantly
inhibited the s.c. and intra-abdominal growth of xenotransplanted
AGS-GFPM2 cells in nude mice. Furthermore, CA4-P
treatment showed a remarkable ability to inhibit gastric tumor
metastasis as well as attenuate p-AKT expression. In conclusion,
our study is the first to find that CA4 inhibited AKT activity in
human gastric cancer cells. The decreased AKT activity correlated
well with the CA4 antitumor growth response and decrease of
metastasis. Further investigation on drugs targeting the PI3
kinase-AKT pathway may provide a new approach for the treatment
of human gastric cancer.

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