A mathematical model of the circadian clock and drug pharmacology to optimize irinotecan administration timing in colorectal cancer

Hesse, Janina; Martinelli, Julien; Aboumanify, Ouda; Ballesta, Annabelle; Relógio, Angela

doi:10.1016/j.csbj.2021.08.051

Cited by 34 publications

(37 citation statements)

References 75 publications

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“…CRC cell lines display a variety of circadian phenotypes which range from a completely disrupted clock to less dramatic alteration in circadian rhythms, which have been reported in published work [ 8 , 9 , 23 , 24 , 25 ]. This variability can also be observed when evaluating the connection between the circadian clock and cancer-related pathways, and the effects are often specific for certain cell lines, as well as specific core-clock gene disruptions [ 8 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Colorectal cancer (CRC) is the third most common cancer, and the second leading cause of cancer death worldwide [ 22 ]. Several studies demonstrated the inter-connection between circadian rhythms and cancer, including CRC [ 8 , 9 , 23 , 24 , 25 , 26 ]. Taking into consideration the lack of knowledge regarding Cynara cardunculus leaf extracts and the circadian clock, in the present study we aimed to investigate if putative anti-cancer effects of C. cardunculus may be related to an underlying circadian regulation in CRC.…”

Section: Introductionmentioning

confidence: 99%

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Antiproliferative Effects of Cynara Cardunculus in Colorectal Cancer Cells Are Modulated by the Circadian Clock

Fuhr

Basti²,

Brás³

et al. 2022

IJMS

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The circadian clock generates 24 h rhythms in behavioural, cellular and molecular processes. Malfunctions of the clock are associated with enhanced susceptibility to cancer, worse treatment response and poor prognosis. Clock-controlled genes are involved in cellular processes associated with tumour development and progression including metabolism of drugs and the cell cycle. Cynara cardunculus, a plant of the Asteraceae family, has been reported to have antiproliferative effects on breast cancer cells. Here, we used the human colorectal cancer (CRC) cell line HCT116 and its knockout variants for different core-clock genes (BMAL1, PER2, NR1D1), to investigate the treatment effect of C. cardunculus lipophilic leaf extract under different clock scenarios. Our results show a direct effect of C. cardunculus on the circadian phenotype of the cells, as indicated by alterations in the phase, amplitude, and period length of core-clock gene oscillations. Furthermore, our data indicate a role for the circadian clock in sensitivity to C. cardunculus treatment. In particular, the treatment inhibited proliferation and induced cytotoxicity and apoptosis in a clock knockout-specific manner, in CRC cells. These results point to a potential effect of C. cardunculus lipophilic leaf extracts as a modulator of the circadian clock, in addition to its anti-proliferative properties.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antiproliferative Effects of Cynara Cardunculus in Colorectal Cancer Cells Are Modulated by the Circadian Clock

Fuhr

Basti²,

Brás³

et al. 2022

IJMS

Self Cite

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“…In another setting, namely a breast cancer xenograft model, the efficacy of erastin, an inhibitor of xCT cystine/glutamate transporter, was improved when administered during the light phase when compared to the dark phase [ 114 ]. In the coming years, pharmacokinetics studies should take this into account, to define the optimal timing of anticancer drug delivery [ 115 ].…”

Section: Current Challenges and Perspectives: How To Define The Most ...mentioning

confidence: 99%

An Overview of the Circadian Clock in the Frame of Chronotherapy: From Bench to Bedside

2022

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Most living organisms in both the plant and animal kingdoms have evolved processes to stay in tune with the alternation of day and night, and to optimize their physiology as a function of light supply. In mammals, a circadian clock relying on feedback loops between key transcription factors will thus control the temporally regulated pattern of expression of most genes. Modern ways of life have highly altered the synchronization of human activities with their circadian clocks. This review discusses the links between an altered circadian clock and the rise of pathologies. We then sum up the proofs of concept advocating for the integration of circadian clock considerations in chronotherapy for health care, medicine, and pharmacotherapy. Finally, we discuss the current challenges that circadian biology must face and the tools to address them.

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“…We think they are complementary because they characterize the dynamics of the DC vaccination at different levels. This strategy has been used in other data-driven computational models (Sobotta et al, 2017, Hesse et al, 2021, Fey et al, 2015.…”

Section: Model Calibration Using Experimental Datamentioning

confidence: 99%

Multi-Level Computational Modeling of Anti-Cancer Dendritic Cell Vaccination Utilized to Select Molecular Targets for Therapy Optimization

Lai

Keller

Santos

et al. 2022

Front. Cell Dev. Biol.

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Dendritic cells (DCs) can be used for therapeutic vaccination against cancer. The success of this therapy depends on efficient tumor-antigen presentation to cytotoxic T lymphocytes (CTLs) and the induction of durable CTL responses by the DCs. Therefore, simulation of such a biological system by computational modeling is appealing because it can improve our understanding of the molecular mechanisms underlying CTL induction by DCs and help identify new strategies to improve therapeutic DC vaccination for cancer. Here, we developed a multi-level model accounting for the life cycle of DCs during anti-cancer immunotherapy. Specifically, the model is composed of three parts representing different stages of DC immunotherapy – the spreading and bio-distribution of intravenously injected DCs in human organs, the biochemical reactions regulating the DCs’ maturation and activation, and DC-mediated activation of CTLs. We calibrated the model using quantitative experimental data that account for the activation of key molecular circuits within DCs, the bio-distribution of DCs in the body, and the interaction between DCs and T cells. We showed how such a data-driven model can be exploited in combination with sensitivity analysis and model simulations to identify targets for enhancing anti-cancer DC vaccination. Since other previous works show how modeling improves therapy schedules and DC dosage, we here focused on the molecular optimization of the therapy. In line with this, we simulated the effect in DC vaccination of the concerted modulation of combined intracellular regulatory processes and proposed several possibilities that can enhance DC-mediated immunogenicity. Taken together, we present a comprehensive time-resolved multi-level model for studying DC vaccination in melanoma. Although the model is not intended for personalized patient therapy, it could be used as a tool for identifying molecular targets for optimizing DC-based therapy for cancer, which ultimately should be tested in in vitro and in vivo experiments.

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A mathematical model of the circadian clock and drug pharmacology to optimize irinotecan administration timing in colorectal cancer

Abstract: Graphical abstract

Cited by 34 publications

References 75 publications

Antiproliferative Effects of Cynara Cardunculus in Colorectal Cancer Cells Are Modulated by the Circadian Clock

Antiproliferative Effects of Cynara Cardunculus in Colorectal Cancer Cells Are Modulated by the Circadian Clock

An Overview of the Circadian Clock in the Frame of Chronotherapy: From Bench to Bedside

Multi-Level Computational Modeling of Anti-Cancer Dendritic Cell Vaccination Utilized to Select Molecular Targets for Therapy Optimization

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