Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma.

Autor:	Gonzalez-Aponte MF; Department of Biology, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA., Damato AR; Department of Biology, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA., Trebucq LL; Laboratorio de Cronobiología, Universidad Nacional de Quilmes-CONICET, B1876BXD, Bernal, Buenos Aires, Argentina., Simon T; Department of Biology, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA., Cárdenas-García SP; Department of Biology, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA., Cho K; Departments of Chemistry and Medicine, Washington University in St. Louis, St. Louis, MO, USA.; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO, USA., Patti GJ; Departments of Chemistry and Medicine, Washington University in St. Louis, St. Louis, MO, USA.; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO, USA., Golombek DA; Laboratorio de Cronobiología, Universidad Nacional de Quilmes-CONICET, B1876BXD, Bernal, Buenos Aires, Argentina.; Laboratorio Interdisciplinario del Tiempo (LITERA), Universidad de San Andrés, Victoria, B1644BID, Buenos Aires, Argentina., Chiesa JJ; Laboratorio de Cronobiología, Universidad Nacional de Quilmes-CONICET, B1876BXD, Bernal, Buenos Aires, Argentina., Herzog ED; Department of Biology, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Sep 17. Date of Electronic Publication: 2023 Sep 17.
DOI:	10.1101/2023.09.13.557630
Abstrakt:	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 6 -Methylguanine-DNA Methyltransferase ( MGMT ) activity in murine and human models of GBM. 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 6 -Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression. 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. Competing Interests: Competing Interests: The authors have no relevant financial or non-financial interests to disclose.
Databáze:	MEDLINE
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