A G-quadruplex-interactive agent, telomestatin (SOT-095), induces telomere shortening with apoptosis and enhances chemosensitivity in acute myeloid leukemia.
Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is up-regulated in the vast majority of human neoplasias but not in normal somatic tissues. Therefore, the telomerase complex represents a promising universal therapeutic target in cancer. Telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to inhibit telomerase activity. We examined G-quadruplex interactive agent, telomestatin (SOT-095), for its ability to inhibit the proliferation of human leukemia cells, including freshly obtained leukemia cells. Telomere length was determined by either the terminal restriction fragment method or flow-FISH, and apoptosis was assessed by flow cytometry. Moreover, chemosensitivity was examined in telomestatin-treated U937 cells before ultimate telomere shortening. Treatment with telomestatin reproducibly inhibited telomerase activity in U937 and NB4 cells followed by telomere shortening. Enhanced chemosensitivity toward daunorubicin and cytosine-arabinoside was observed in telomestatin-treated U937 cells, before ultimate telomere shortening. Telomere shortening associated with apoptosis by telomestatin was evident in some freshly obtained leukemia cells from acute myeloid leukemia patients, regardless of sub-types of AML and post-myelodysplasia AML. These results suggest that disruption of telomere maintenance by telomestatin limits the cellular lifespan of AML cells, as well. However, in a minority of AML patients apoptosis was not evident, thus indicating that resistant mechanism might exist in some freshly obtained AML cells. Therefore, further investigation of telomestatin as a therapeutic agent is warranted.
Sumi
M
M
First Department of Internal Medicine, Tokyo Medical University, Tokyo 160-0023, Japan.
Tauchi
T
T
Sashida
G
G
Nakajima
A
A
Gotoh
A
A
Shin-Ya
K
K
Ohyashiki
J H
JH
Ohyashiki
K
K
D000208:Acute Disease; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology; D004268:DNA-Binding Proteins; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D010080:Oxazoles; C431888:telomestatin; D003561:Cytarabine; D019098:Telomerase; D003630:Daunorubicin