Leukemic cells with increased telomerase activity exhibit resistance to imatinib.
Imatinib mesylate (imatinib), previously known as STI571 (Gleevec), is currently utilized in the treatment of chronic myeloid leukemia (CML). However, its effect on telomerase activity and the correlation of this to its observed antitumor effect has yet to be defined. We investigated the effects of this agent on human telomerase reverse transcriptase (hTERT) expression and telomerase activity and found that it significantly down-regulated telomerase activity in both K562 cells and primary leukemic cells. The telomerase activity of primary leukemic cells from CML patients in blastic crisis showed less suppression than that of cells from patients in chronic phase. Additionally, data also demonstrate that inhibition of telomerase was due to the direct action of imatinib on hTERT transcription, rather than an increase in cell death. These results suggest a novel mechanism in the antitumor activity of imatinib and may provide a basis for future development of anti-telomerase therapies, as well as leading to better understanding of the regulation of telomerase in leukemic cells.
Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan. yamadao@lab.twmu.ac.jp
Osamu
O
Yamada
Kiyotaka
K
Kawauchi
Masaharu
M
Akiyama
Kohji
K
Ozaki
Toshiko
T
Motoji
Tomoko
T
Adachi
Eizo
E
Aikawa
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001752:Blast Crisis; D019008:Drug Resistance, Neoplasm; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C509186:TERT protein, human; D019098:Telomerase