Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling

Jul 5, 2015Molecular cancer therapeutics

Timing Factors in Cancer Drug Treatment Identified Using Lab Tests and Mathematical Models

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Abstract

A four-fold difference in irinotecan-induced apoptosis was observed based on drug timing relative to circadian rhythms.

Circadian rhythms significantly influenced the bioactivation, detoxification, and transport of irinotecan in colorectal cancer cells.
Pharmacokinetics and pharmacodynamics of irinotecan showed statistically significant changes based on the timing of drug administration.
The expression of the clock gene BMAL1 was directly linked to variations in irinotecan cytotoxicity, with the least apoptosis occurring when drug exposure aligned with BMAL1 mRNA nadir.
Silencing BMAL1 completely abolished the chronopharmacology mechanisms associated with irinotecan.
Mathematical modeling identified circadian bioactivation and detoxification as critical factors in the chronopharmacology of irinotecan.

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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.

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Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling

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