A novel anticancer ribonucleoside, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine, enhances radiation-induced cell death in tumor cells.
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.
Inanami
Osamu
O
Laboratory of Radiation Biology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
Iizuka
Daisuke
D
Iwahara
Akiko
A
Yamamori
Tohru
T
Kon
Yasuhiro
Y
Asanuma
Taketoshi
T
Matsuda
Akira
A
Kashiwakura
Ikuo
I
Kitazato
Kenji
K
Kuwabara
Mikinori
M
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
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