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.