Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling
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Abstract
Cancer chronotherapy aims at enhancing tolerability and efficacy of anticancer drugs through their delivery according to circadian clocks. However, mouse and patient data show that lifestyle, sex, genetics, drugs, and cancer can modify both host circadian clocks and metabolism pathways dynamics, and thus the optimal timing of drug administration. The mathematical modeling of chronopharmacology could indeed help moderate optimal timing according to patient-specific determinants. Here, we combine in vitro and in silico methods, in order to characterize the critical molecular pathways that drive the chronopharmacology of irinotecan, a topoisomerase I inhibitor with complex metabolism and known activity against colorectal cancer. Large transcription rhythms moderated drug bioactivation, detoxification, transport, and target in synchronized colorectal cancer cell cultures. These molecular rhythms translated into statistically significant changes in pharmacokinetics and pharmacodynamics according to in vitro circadian drug timing. The top-up of the multiple coordinated chronopharmacology pathways resulted in a four-fold difference in irinotecan-induced apoptosis according to drug timing. Irinotecan cytotoxicity was directly linked to clock gene BMAL1 expression: The least apoptosis resulted from drug exposure near BMAL1 mRNA nadir (P < 0.001), whereas clock silencing through siBMAL1 exposure ablated all the chronopharmacology mechanisms. Mathematical modeling highlighted circadian bioactivation and detoxification as the most critical determinants of irinotecan chronopharmacology. In vitro–in silico systems chronopharmacology is a new powerful methodology for identifying the main mechanisms at work in order to optimize circadian drug delivery. Mol Cancer Ther; 14(9); 2154–64. ©2015 AACR.
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Fauteck, J. (2022) · Springer eBooks · doi:10.1007/978-3-662-61417-4_13 · Cited by 1 · see citing works
Circadian Regulation of Temozolomide Sensitivity in Glioblastoma
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Time matters: chrono-pharmacotherapy as precision medicine
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Chronotherapy in Oncology: Aligning Cancer Treatment with Biological Time
Belančić, A., Golčić, M., Fajkić, A., Bračić, V., Skelin, M., Markotić, A., Ćavar, I., Trivanović, D., & Mikolašević, I. (2026) · Journal of Personalized Medicine · doi:10.3390/jpm16080428
- Authors
- Dulong, S., Ballesta, A., Okyar, A., & Lévi, F.
- Affiliations
- Université Paris-Sud (FR)
- University of Warwick (GB)
- 1INSERM, UMR-SO776 “Rythmes biologiques et cancers,” CNRS Campus, Villejuif, France.
- Venue
- Molecular Cancer Therapeutics
- Published
- 2015-09-01
- Volume
- 14
- Issue
- 9
- Pages
- 2154-2164
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2152208758
- Cited by
- 68
- References
- 37
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 9 · 2020: 6 · 2019: 11 · 2018: 5 · 2017: 5 · 2016: 4
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Keywords
- cancer chronotherapy, circadian clock, irinotecan, topoisomerase I inhibitor, Bmal1, colorectal cancer, drug metabolism, pharmacokinetics, pharmacodynamics, apoptosis, siRNA knockdown
- MeSH terms
- Irinotecan, Animals, Antineoplastic Agents, Camptothecin, DNA Topoisomerases, Type I, Humans, Models, Theoretical, Neoplasms, Gene Expression Regulation, Neoplastic, Apoptosis, Cell Line, Tumor, Mice, Drug Chronotherapy, Circadian Clocks, In Vitro Techniques
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