Anticancer mechanisms of 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl) cytosine (ECyd, TAS-106).
We investigated the molecular mechanisms of cell death induced by 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106), a potent inhibitor of RNA synthesis, using mouse mammary tumor FM3A cells and human fibrosarcoma HT1080 cells. ECyd induced the characteristics of apoptosis on these cells, such as morphological changes, DNA fragmentations and caspase-3-like protease activation. General caspases inhibitor, Z-Asp-CH2-DCB inhibited cell death. Interestingly, we also found that ECyd induced rRNA fragmentation. The cleavage pattern of rRNA resembled in that mediated by RNase L. On the other hands, it was suggested that caspase-1, 3, 8 and 9 concerned with ECyd-induced apoptosis through mitochondria. ECyd-induced rRNA fragmentation was inhibited by general caspases inhibitor (Z-Asp-CH2-DCB) and caspase-5 inhibitor (Z-WEHD-fmk). So it is clear that caspase-5 (ICErel III/TY), member of ICE (Interleukin-1 beta-converting enzyme) protease, activated pathway concerned with ECyd-induced rRNA fragmentation. These results indicate that antitumor mechanisms of ECyd are involved in caspase-dependent activation of RNase L. rRNA fragmentation may occur one of the death events, as a result of inhibition of RNA synthesis and play an important role in the antitumor activity of ECyd.
Naito
Tomoharu
T
Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Yokogawa
Tatsushi
T
Kim
Hey-Sook
HS
Futagami
Michiko
M
Wataya
Yusuke
Y
Matsuda
Akira
A
Fukushima
Masakazu
M
Kitade
Yukio
Y
Sasaki
Takuma
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004722:Endoribonucleases / Q000378:metabolism; D006868:Hydrolysis; D014407:Tumor Cells, Cultured
C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D000970:Antineoplastic Agents; D003562:Cytidine; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease