title: Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling.
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.
authors.affiliation: INSERM, UMR-SO776 "Rythmes biologiques et cancers," CNRS Campus, Villejuif, France. Université Paris-Sud, Orsay, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dulong
authors.affiliation: Warwick Systems Biology Centre, Coventry, United Kingdom. Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Ballesta
authors.affiliation: INSERM, UMR-SO776 "Rythmes biologiques et cancers," CNRS Campus, Villejuif, France. Université Paris-Sud, Orsay, France. Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey.
authors.forename: Alper
authors.initials: A
authors.lastname: Okyar
authors.affiliation: INSERM, UMR-SO776 "Rythmes biologiques et cancers," CNRS Campus, Villejuif, France. Université Paris-Sud, Orsay, France. Warwick Systems Biology Centre, Coventry, United Kingdom. Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom. Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département d'oncologie médicale, Hôpital Paul Brousse, Villejuif, France. f.levi@warwick.ac.uk.
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000187:drug effects / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D055870:Drug Chronotherapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D051379:Mice; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin