Epigenetic silencing of telomerase and a non-alkylating agent as a novel therapeutic approach for glioma.
5-Aza-2'-deoxycytidine (5azadC) inhibits DNA methyltransferase and subsequently induces the expression of genes silenced by methylation. While treatment with 5azadC downregulated hTERT and upregulated MGMT expression in two glioma cell lines, there was no change in the expression of these two genes in the normal cell line. However, cell viability was reduced as a result of 5azadC treatment in all three cell lines. 5azadC treatment reduced telomerase expression and activity and subsequently enhanced chemosensitivity towards cisplatin, taxol and tamoxifen but not with the alkylating agents temozolomide (TMZ), carmustine and chlorambucil. To further evaluate the effect of these findings, the level of hTERT and MGMT expression was measured in a recurrent anaplastic ependymoma, seven glioblastoma and two normal brain tissues. While four of eight gliomas and one of the normal tissues expressed MGMT, hTERT was expressed in all gliomas but not in the normal brain tissue. Results of this study suggest that taxol together with 5azadC may be a good therapeutic combination for glioma. In addition, the work on cell lines can be repeated on tissues utilizing hTERT as the therapeutic target for demethylation using 5azadC in glioma.
Patel
Rahima
R
Brain Tumour North West, Faculty of Science, University of Central Lancashire, Preston, UK.
Shervington
Leroy
L
Lea
Robert
R
Shervington
Amal
A
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects* / Q000502:physiology; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D019098:Telomerase / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D000077209:Decitabine; D008780:Methyltransferases; D019098:Telomerase; D001374:Azacitidine; D017239:Paclitaxel