Modeling the Circadian Control of the Cell Cycle and Its Consequences for Cancer Chronotherapy

SIMPLE SUMMARY: The circadian clock controls many physiological processes including the cell division cycle. Healthy cells thus have a higher propensity to divide at certain times during the day. In many cancer cells, the circadian entrainment of the cell division cycle is impaired or lost, due to a disrupted clockwork. Here, we use a computational model describing the molecular network governing the progression into the successive phases of the cell cycle and investigate, through numerical simulations, the consequences of the circadian control on the dynamics of the cell cycle. Our results allow us to predict the optimal timing for the application of anti-cancer drugs that target specific phases of the cell division cycle and highlight the importance of better characterization of cellular heterogeneity and synchronization in cell populations in order to design successful chronopharmacological protocols. ABSTRACT: The mammalian cell cycle is governed by a network of cyclin/Cdk complexes which signal the progression into the successive phases of the cell division cycle. Once coupled to the circadian clock, this network produces oscillations with a 24 h period such that the progression into each phase of the cell cycle is synchronized to the day–night cycle. Here, we use a computational model for the circadian clock control of the cell cycle to investigate the entrainment in a population of cells characterized by some variability in the kinetic parameters. Our numerical simulations showed that successful entrainment and synchronization are only possible with a sufficient circadian amplitude and an autonomous period close to 24 h. Cellular heterogeneity, however, introduces some variability in the entrainment phase of the cells. Many cancer cells have a disrupted clock or compromised clock control. In these conditions, the cell cycle runs independently of the circadian clock, leading to a lack of synchronization of cancer cells. When the coupling is weak, entrainment is largely impacted, but cells maintain a tendency to divide at specific times of day. These differential entrainment features between healthy and cancer cells can be exploited to optimize the timing of anti-cancer drug administration in order to minimize their toxicity and to maximize their efficacy. We then used our model to simulate such chronotherapeutic treatments and to predict the optimal timing for anti-cancer drugs targeting specific phases of the cell cycle. Although qualitative, the model highlights the need to better characterize cellular heterogeneity and synchronization in cell populations as well as their consequences for circadian entrainment in order to design successful chronopharmacological protocols.