Transcriptional activation of cyclin-dependent kinase inhibitor, p21waf1 gene by treatment with a differentiation inducing agent, vesnarinone in a human salivary gland cancer cell line.
Recently, a new concept for cancer therapy termed "tumor dormancy therapy" has been proposed. The concept of this therapy is to prolong the survival time of cancer patients while maintaining their quality of life. We have been developing a differentiation-inducing therapy, which is included in the tumor dormancy therapy, for salivary gland cancer. In this study, we examined the effect of a differentiation-inducing drug, Vesnarinone on the growth of several cancer cells, and examined the molecular mechanism by which Vesnarinone induces the cyclin dependent kinase inhibitor, p21waf1 in the cancer cells. Vesnarinone significantly suppressed the growth of TYS (salivary gland cancer cells), PC3 (prostate cancer cells), and A431 (squamous cell cancer cells). Furthermore, Vesnarinone dose-dependently enhanced the expression of p21waf1 mRNA in TYS cells. Using the luciferase reporter assay it was found that the enhancement of p21waf1 mRNA expression by Vesnarinone was through direct transcriptional activation of the p21waf1 promoter. Thus, analyzing the molecular mechanisms of differentiation inducing drugs may lead to the development of a new therapeutic strategy for several human malignancies, including salivary gland cancer.
Dept. of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Mibu, Shimo-tsuga, Tochigi, Japan.
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Omotehara
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Nakashiro
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Uchida
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Hino
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Fujimori
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Kawamata
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D016213:Cyclins / Q000235:genetics*; D004791:Enzyme Inhibitors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D010957:Plasmids; D011719:Pyrazines; D011804:Quinolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000473:pathology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D011719:Pyrazines; D011804:Quinolines; D012333:RNA, Messenger; C041667:vesnarinone; D018844:Cyclin-Dependent Kinases