CDK inhibitor enhances the sensitivity to 5-fluorouracil in colorectal cancer cells.
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.
Takagi
Koichi
K
Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Sowa
Yoshihiro
Y
Cevik
Ozgur Muhammer
OM
Nakanishi
Ryoko
R
Sakai
Toshiyuki
T
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D004794:Enzyme Repression; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
D000964:Antimetabolites, Antineoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050684:E2F Transcription Factors; D007093:Imidazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C433985:SU 9516; D013940:Thymidylate Synthase; D018844:Cyclin-Dependent Kinases; D005472:Fluorouracil