3'-Azido-2',3'-dideoxynucleoside 5'-triphosphates inhibit telomerase activity in vitro, and the corresponding nucleosides cause telomere shortening in human HL60 cells.
Telomerase adds telomeric DNA repeats to the ends of linear chromosomal DNA. 3'-Azido-3'-deoxythymidine 5'-triphosphate (AZTTP) is a known telomerase inhibitor. To obtain more selective and potent inhibitors that can be employed as tools for studying telomerase, we investigated the telomerase-inhibitory effects of purine nucleosides bearing a 3'-down azido group: 3'-azido-2',3'-dideoxyguanosine (AZddG) 5'-triphosphate (AZddGTP), 3'-azido-2',3'-dideoxy-6-thioguanosine (AZddSG) 5'-triphosphate (AZddSGTP), 3'-azido-2',3'-dideoxyadenosine (AZddA) 5'-triphosphate (AZddATP) and 3'-azido-2',3'-dideoxy-2-aminoadenosine (AZddAA) 5'-triphosphate (AZddAATP). Of these, AZddGTP showed the most potent inhibitory activity against HeLa cell telomerase. AZddGTP was significantly incorporated into the 3'-terminus of DNA by partially purified telomerase. However, AZddGTP did not exhibit significant inhibitory activity against DNA polymerases alpha and delta, suggesting that AZddGTP is a selective inhibitor of telomerase. We also investigated whether long-term treatment with these nucleosides could alter telomere length and growth rates of human HL60 cells in culture. Southern hybridization analysis of genomic DNA prepared from cells cultured in the presence of AZddG and AZddAA revealed reproducible telomere shortening.
Liu
Xiaohong
X
Biotechnology Research Center, Teikyo University of Science and Technology, Uenohara, Yamanashi, Japan.
Takahashi
Hazuki
H
Harada
Yoko
Y
Ogawara
Tsukasa
T
Ogimura
Yuta
Y
Mizushina
Yoshiyuku
Y
Saneyoshi
Mineo
M
Yamaguchi
Toyofumi
T
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000737:chemistry / Q000494:pharmacology*; D054306:Dideoxynucleotides / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000737:chemistry / Q000378:metabolism*; D015215:Zidovudine / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D054306:Dideoxynucleotides; D004791:Enzyme Inhibitors; C055319:3'-azido-2,6-diaminopurine-2',3'-dideoxyriboside; D015215:Zidovudine; D016048:Dideoxyadenosine; C051073:3'-azido-2',3'-dideoxyguanosine; D004247:DNA; D019098:Telomerase