JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 23, 2007; DOI: 10.1124/jpet.107.124966

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.107.124966v1
323/1/365    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lin, H.-L.
Right arrow Articles by Chi, C.-W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lin, H.-L.
Right arrow Articles by Chi, C.-W.


Received for publication April 27, 2007.
Revised July 19, 2007.
Accepted for publication July 19, 2007.

Combretastatin A4-Induced Differential Cytotoxicity and Reduced Metastatic Ability by Inhibition of AKT Function in Human Gastric Cancer Cells

Heng-Liang Lin 1, Shih-Hwa Chiou 2, Chew-Wun Wu 3, Wen-Bin Lin 2, Li-Hsin Chen 1, Yi-Ping Yang 2, Ming-Long Tsai 2, Yih-Huei Uen 4, Jing-Ping Liou 5, Chin-Wen Chi 6*

1 Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan 2 Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 3 School of Medicine, National Yang-Ming University, Taipei, Taiwan 4 Chi Mei Medical Center, Tainan, Taiwan 5 Department of Medicinal Chemistry, School of Pharmacy, Taipei Medical University, Taipei, Taiwan. 6 Taipei Veteran General Hospital

* Address correspondence to: E-mail: cwchi{at}vghtpe.gov.tw

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 anti-tumor mechanisms. Nine human gastric cancer cell lines including two metastatic gastric cancer cell lines (AGS-GFPM1/2) constitutively expressed green fluorescence protein (GFP) were used. These metastatic AGS-GFPM1/2 cells expressed a higher level of p-AKT. Our results showed that CA4 (0.02-20 µM) 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, PI3K inhibitor (LY294002), specific AKT inhibitor and 0.2-20 µM 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 subcutaneous 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 anti-tumor growth response and decrease of metastasis. Further investigation on drugs targeting PI3 kinase-AKT pathway may provide a new approach for the treatment of human gastric cancer.


Key words: AKT, Chemotherapy, Combretastatin A4, Gastric cancer, Green fluorescence protein, p-AKT




Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics.