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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Institutes of Pharmacology (H.-L.L., L.-H.C., C.-W.C.) and Clinical Medicine (S.-H.C., Y.-P.Y.), School of Medicine (C.-W.W.), National Yang-Ming University, Taipei, Taiwan; Departments of Medical Research and Education (S.-H.C., W.-B.L., Y.-P.Y., M.-L.T., C.-W.C.) and General Surgery (C.-W.W.), Taipei Veterans General Hospital, Taipei, Taiwan; Chi Mei Medical Center, Tainan, Taiwan (Y.-H.U.); and Department of Medicinal Chemistry, School of Pharmacy, Taipei Medical University, Taipei, Taiwan (J.-P.L.)

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 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, 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 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 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.

Address correspondence to: Dr. Chin-Wen Chi, Department of Medical Research and Education, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan. E-mail: cwchi{at}vghtpe.gov.tw

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