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Identification of circadian determinants of cancer chronotherapy through in vitro chronopharmacology and mathematical modeling

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Dulong, S., Ballesta, A., Okyar, A. and Lévi, Francis A. (2015) Identification of circadian determinants of cancer chronotherapy through in vitro chronopharmacology and mathematical modeling. Molecular Cancer Therapeutics, 14 (9). pp. 2154-2164. doi:10.1158/1535-7163.MCT-15-0129

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Official URL: http://dx.doi.org/10.1158/1535-7163.MCT-15-0129

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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.

Item Type: Journal Article
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine
Faculty of Medicine > Warwick Medical School
Journal or Publication Title: Molecular Cancer Therapeutics
Publisher: American Association for Cancer Research
ISSN: 1535-7163
Official Date: 3 July 2015
Dates:
DateEvent
3 July 2015Published
23 June 2015Accepted
11 February 2015Submitted
Volume: 14
Number: 9
Page Range: pp. 2154-2164
DOI: 10.1158/1535-7163.MCT-15-0129
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access

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