Inhibition of telomerase activity in malignant glioma cells correlates with their sensitivity to temozolomide.
Temozolomide (TMZ, 3,4-dihydro-3-methyl-4-oxoimidazo [5,1-d]-as-tetrazine-8-carboxamide) is a new alkylating agent with promising antitumour efficacy for malignant gliomas. The resistance of tumour cells to TMZ is primarily associated with levels of the alkylguanine alkyltransferase (AGT). O(6)-benzylguanine (O(6)-BG), an inhibitor for AGT, reduced resistance to TMZ. Recently, it has been demonstrated that chemosensitivity of tumour cells is related to a decline in telomerase activity. However, it is unknown if TMZ sensitivity of malignant glioma cells correlates with telomerase. In this study, using malignant glioma cells with low levels of AGT (U373-MG and U87-MG) and high levels of AGT (T98G), we investigated the association among AGT, telomerase, and TMZ sensitivity. U373-MG and U87-MG cells were sensitive to TMZ (IC(50) for a 2-day treatment=100 microM), while T98G cells were resistant to TMZ (IC(50) for a 2-day treatment >500 microM). Treatment with TMZ (100 microM) suppressed telomerase activity in U373-MG and U87-MG cells in a time-dependent manner, but not in T98G cells. The downregulation of telomerase activity in U373-MG and U87-MG cells was due to inhibition of the human telomerase reverse-transcriptase (hTERT) gene expression at the transcriptional level. This inhibitory effect was induced by interfering with transcription factor Sp1 binding sites of the hTERT core promoter. Interestingly, O(6)-BG not only sensitised T98G cells to TMZ, but also suppressed telomerase activity. These findings suggest that response of malignant glioma cells to TMZ can be monitored by reduction in telomerase activity. Therefore, quantification of telomerase activity during or after treatment with TMZ may be a useful marker to detect treatment efficacy.
Kanzawa
T
T
Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY 10029, USA.
Germano
I M
IM
Kondo
Y
Y
Ito
H
H
Kyo
S
S
Kondo
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S
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D000077204:Temozolomide; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D019098:Telomerase; D000077204:Temozolomide