Telomerase inhibition enhances apoptosis in human acute leukemia cells: possibility of antitelomerase therapy.
Telomerase is a ribonucleoprotein enzyme that maintains protective structures at the ends of eukaryotic chromosomes. We examined the impact of telomerase inhibition by the dominant-negative human catalytic subunit of telomerase (DN-hTERT) on the biological features of acute leukemia. We introduced vectors encoding dominant- negative (DN)-hTERT, wild-type (WT)-hTERT, or a control vector expressing only a drug-resistant marker into a telomerase-positive human acute lymphoblastic leukemia cell line, HAL-01. Expression of DN-hTERT dramatically inhibited telomerase activity, leading to apoptotic cell death. Mutant telomerase expression also enhanced daunorubicin-induced apoptosis. Nude mice (n=5 per group) received subcutanous implants of HAL-01 cells expressing the control vector or DN-hTERT or WT-hTERT. Implantation of HAL-01 cells expressing control vector (n=5) rapidly produced tumors, whereas implantation of those expressing DN-hTERT (n=5) did not. Thus, telomerase inhibition both growth of HAL-01 cells in vitro and tumorigenic capacity in vivo. Furthermore, the G-quadruplex-interactive telomerase-specific inhibitor, telomestatin, shortened the telomere length and induced apoptosis in freshly isolated primary acute leukemia cells. These results suggest that antitelomerase therapy may be useful in some acute leukemias in combination with antileukemic agents such as daunorubicin.
Nakajima
A
A
First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Japan.
Tauchi
T
T
Sashida
G
G
Sumi
M
M
Abe
K
K
Yamamoto
K
K
Ohyashiki
J H
JH
Ohyashiki
K
K
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004268:DNA-Binding Proteins; D003630:Daunorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005799:Genes, Dominant; D015316:Genetic Therapy; D006801:Humans; D007938:Leukemia / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D019098:Telomerase / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000494:pharmacology*; D016615:Telomere / Q000187:drug effects / Q000648:ultrastructure; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D019098:Telomerase; D003630:Daunorubicin