Circadian control of xenobiotic carcinogenesis and cancer pharmacology

author: Francis Lévi, Warwick Medical School, University of Warwick
published: July 21, 2014,   recorded: May 2014,   views: 46


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Xenobiotic metabolism and detoxification, as well as cell cycle events, DNA repair, apoptosis and angiogenesis are rhythmically controlled by the Circadian Timing System (CTS), a hierarchical and coordinated network of cellular clocks. Interwoven transcription/translation feedback loops involving 15 clock genes rhythmically moderate metabolism and effects of carcinogenic xenobiotics and anticancer drugs. Anatomic, physiologic or molecular CTS disruption accelerates cancer processes, including initiation, promotion and progression in experimental models, while, CTS reinforcement halts these processes. These experimental data support a role for the CTS in the increased cancer risk associated to shift work. Chronotherapeutics aims at improving outcomes through the delivery of medicines according to circadian rhythms. Indeed, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability. These findings support a paradigm for cancer therapy that is specific to chronotherapy,i.e. "the lesser the toxicity, the better the efficacy" (Lévi et al. Annu Rev Pharm Toxicol 2010). While most chronopharmacologic effects have been shown in light-dark synchronized mammals, the relevance of clock robustness and drug timing for cancer chronotherapeutics is now systematically studied in synchronized cell cultures, using clock gene silencing with RNA interference. Recent studies reveal the molecular clock dependency of irinotecan bioactivation, detoxification, transport, and molecular target interactions. They further enable a precise quantification and mathematical modeling of chronoPK-PD relations at cell population levels (Dulong et al. submitted). Stochastic modeling of mouse and human chronoPKPD reveals that optimal chronotherapeutic effects require circadian entrainment to be robust in healthy cells and weak in cancer cells, a finding supported by experimental data. Moreover host clocks differ according to sex and genetic background, and can further be altered with xenobiotics as a function of dose and circadian timing. We find that the combined circadian expressions of core clock genes Rev- Erbα and Bmal1 are proper predictors of optimal drug timing in mice from different strains and sex, using irinotecan as a model (Li et al. Cancer Res 2013). Current studies support the relevance of the physiological rhythms that reset both clock genes as clinically relevant CTS biomarkers both for the detection of cancer risk and the prediction of optimal chronotherapeutics schedule.

Support: C5SYS project (ANR and ERASysBio+ initiative, an EU ERA-NET in FP7); Ca

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