title: A novel anticancer ribonucleoside, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine, enhances radiation-induced cell death in tumor cells.
abstract: 1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS106) is a newly developed anti-tumor agent that targets RNA synthesis. We report here that a low dose of ECyd induces radiosensitization of caspase-dependent apoptosis and reproductive cell death in cells of the gastric tumor cell lines MKN45 and MKN28 and murine rectum adenocarcinoma Colon26. Flow cytometry demonstrated that TAS106 induced the abrogation of the X-ray-induced G(2)/M checkpoint. Western blot analysis showed that X rays increased the expression of cyclin B1, phospho-Cdc2 and Wee1, whereas co-treatment with X rays and TAS106 decreased the expression of these cell cycle proteins associated with the G(2)/M checkpoint. Furthermore, TAS106 was shown to decrease the radiation-induced expression of survivin but not Bcl2 and BclX(L) regardless of TP53 status and cell type. Overexpression of wild-type survivin in MKN45 cells inhibited the induction of apoptosis induced by co-treatment with X rays and TAS106. These results suggest that TAS106 enhances X-ray-induced cell death through down-regulation of survivin and abrogation of the cell cycle machinery.
authors.affiliation: Laboratory of Radiation Biology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Inanami
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iizuka
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwahara
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamori
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kon
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Asanuma
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kashiwakura
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitazato
authors.forename: Mikinori
authors.initials: M
authors.lastname: Kuwabara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000528:radiation effects; D020169:Caspases / Q000502:physiology; D018797:Cell Cycle Proteins / Q000032:analysis; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000032:analysis; D056744:Cyclin B1; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000032:analysis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000077022:Survivin; D014965:X-Rays
chemical_list: C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011838:Radiation-Sensitizing Agents; D000077022:Survivin; D003562:Cytidine; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C499348:Wee1 protein, mouse; D020169:Caspases