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: Sandrine Dulong, Annabelle Ballesta, Alper Okyar, Francis Lévi
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 9 Pg. 2154-64 (Sep 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 26141947 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Irinotecan
• DNA Topoisomerases, Type I
• Camptothecin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects, genetics)
• Camptothecin (analogs & derivatives, pharmacology, therapeutic use)
• Cell Line, Tumor
• Circadian Clocks (drug effects, genetics)
• DNA Topoisomerases, Type I (metabolism)
• Drug Chronotherapy
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• In Vitro Techniques
• Irinotecan
• Mice
• Models, Theoretical
• Neoplasms (drug therapy, genetics, metabolism)