Effect of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (vesnarinone) on the growth of gastric cancer cell lines.
Vesnarinone (OPC-8212; 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone ) is a synthetic oral cardiotonic agent that has been used for the treatment of patients with congestive heart failure. Six days of treatment with 30 microg/ml of vesnarinone induced 20-80% growth inhibitions in five out of six gastric carcinoma cell lines examined. Cell cycle analysis revealed that the vesnarinone-sensitive TMK-1 gastric cancer cell line exhibited a significant G0-G1 arrest without evidence of apoptotic cell death induction after 48 h of treatment. Interestingly, this phenomenon was preceded by a marked reduction in the expression of cyclin A, D1 and E as well as cyclin-dependent kinase 2 (CDK2). On the other hand, no significant change was observed in the expression of p21(Waf1/Cip1), p27Kip1 nor various growth factors and their receptor genes. Overall these results indicate that vesnarinone inhibits the growth of gastric cancer cells by down-regulating G1 cyclins and CDK2 to induce G0-G1 arrest through a pathway different from that of cyclin inactivation by p21(Waf1/Cip1) or p27Kip1.
First Department of Pathology, Hiroshima University School of Medicine, Japan. hyoko@mcai.med.hiroshima-u.ac.jp
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H
Yokozaki
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Ito
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Ono
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Hayashi
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Tahara
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015152:Blotting, Northern; D002277:Carcinoma / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000473:pathology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011719:Pyrazines; D011804:Quinolines; D012333:RNA, Messenger; C041667:vesnarinone