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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.
Highlights
Most biologic functions in experimental rodents and humans are rhythmically moderated by the Circadian Timing System (CTS) over 24 hours [1]
We studied the sensitivity of all model parameters—except Km's of enzymatic reactions—together with that of irinotecan initial concentration and exposure duration (Texpo)
In cells treated with control siRNA, the 3 clock genes and the 4 pharmacologic genes displayed circadian rhythms in their mRNA expression with amplitude values A ranging from 40% to 80% of mean values M (Figs. 2 and Supplementary Table S1)
Summary
Most biologic functions in experimental rodents and humans are rhythmically moderated by the Circadian Timing System (CTS) over 24 hours [1]. Circadian timing is especially relevant for anticancer drugs whose optimal dose and delivery schedule are most critical for safely achieving best antitumor efficacy [2]. Up-to-severalfold changes in treatment tolerability and/or efficacy were found according to dosing time for 40 anticancer drugs in rodents [2]. The administration of anticancer agents at the circadian time when they were the safest achieved best efficacy both in rodents [4] and in cancer patients [5,6,7,8]. A systematic mapping of the critical pathways of anticancer drug chronopharmacology and their molecular clock control is required for optimizing treatment effects through tailoring circadian drug delivery to individual CTS
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