Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways.
The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.
Tauchi
Tetsuzo
T
First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. tauchi@tokyo-med.ac.jp
Shin-Ya
Kazuo
K
Sashida
Goro
G
Sumi
Masahiko
M
Nakajima
Akihiro
A
Shimamoto
Takashi
T
Ohyashiki
Junko H
JH
Ohyashiki
Kazuma
K
D017209:Apoptosis / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D010080:Oxazoles / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010080:Oxazoles; D025521:Tumor Suppressor Proteins; C431888:telomestatin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase