Abstract
Thymidylate synthase (TS) is a dNTP synthetic enzyme and is also a target enzyme of 5-fluorouracil (5-FU). 5-FU is one of the anticancer agents most frequently used for the treatment of colorectal cancers. However, the clinical rate of response to its use as a single agent is not exceptionally high. Therefore, various combination chemotherapies have been devised. The elevated expression of TS in cancer cells is a serious obstacle in the clinical use of 5-FU. In the present study, TS expression was up-regulated by the knockout of the p21WAF1/CIP1 gene in human colorectal cancer HCT116 cells, suggesting that TS expression is mediated through the inhibition of cyclin-dependent kinase (CDK). Based on these findings, we tested whether the CDK inhibitor (CDKI) SU9516, acted as a suppressor of TS. SU9516 effectively reduced the expression of TS in a dose-dependent manner. Furthermore, the reduction of TS expression resulted in enhancement of the sensitivity to 5-FU in human colon cancer DLD-1 cells. Thus, SU9516 might be a promising compound for combination chemotherapy with 5-FU.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimetabolites, Antineoplastic / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Cell Proliferation / drug effects
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Colorectal Neoplasms / drug therapy
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Colorectal Neoplasms / enzymology*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / pathology
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / metabolism
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Dose-Response Relationship, Drug
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E2F Transcription Factors / genetics
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E2F Transcription Factors / metabolism
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Enzyme Repression
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Fluorouracil / analogs & derivatives
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Fluorouracil / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Silencing
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HCT116 Cells
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Humans
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Imidazoles / pharmacology
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Indoles / pharmacology
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Protein Kinase Inhibitors / pharmacology
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RNA, Messenger / metabolism
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Thymidylate Synthase / antagonists & inhibitors*
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Thymidylate Synthase / biosynthesis
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Thymidylate Synthase / genetics
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Transfection
Substances
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Antimetabolites, Antineoplastic
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Cyclin-Dependent Kinase Inhibitor p21
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E2F Transcription Factors
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Imidazoles
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Indoles
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Protein Kinase Inhibitors
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RNA, Messenger
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SU 9516
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Thymidylate Synthase
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Cyclin-Dependent Kinases
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Fluorouracil