Article ; Online: Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma.
2024 Volume 166, Issue 3, Page(s) 419–430
Abstract: Background: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve ... ...
| Abstract | Background: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O Methods and results: In vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O Conclusion: We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity and that scoring MGMT methylation status requires controlling for time of day of biopsy. |
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| MeSH term(s) | Humans ; Animals ; Mice ; Glioblastoma/drug therapy ; Glioblastoma/genetics ; Glioblastoma/pathology ; Temozolomide/pharmacology ; Temozolomide/therapeutic use ; Dacarbazine/therapeutic use ; Antineoplastic Agents, Alkylating/pharmacology ; Antineoplastic Agents, Alkylating/therapeutic use ; O(6)-Methylguanine-DNA Methyltransferase/genetics ; Retrospective Studies ; ARNTL Transcription Factors/genetics ; ARNTL Transcription Factors/metabolism ; Methylation ; DNA Repair Enzymes/genetics ; DNA Repair Enzymes/metabolism ; DNA Modification Methylases/genetics ; DNA Modification Methylases/metabolism ; DNA Methylation ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism |
| Chemical Substances | Temozolomide (YF1K15M17Y) ; Dacarbazine (7GR28W0FJI) ; Antineoplastic Agents, Alkylating ; O(6)-Methylguanine-DNA Methyltransferase (EC 2.1.1.63) ; ARNTL Transcription Factors ; DNA Repair Enzymes (EC 6.5.1.-) ; DNA Modification Methylases (EC 2.1.1.-) ; MGMT protein, human (EC 2.1.1.63) ; Tumor Suppressor Proteins |
| Language | English |
| Publishing date | 2024-01-26 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 604875-4 |
| ISSN | 1573-7373 ; 0167-594X |
| ISSN (online) | 1573-7373 |
| ISSN | 0167-594X |
| DOI | 10.1007/s11060-023-04535-9 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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