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The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise.

Puszynski K, Gandolfi A, d'Onofrio A - PLoS Comput. Biol. (2014)

Bottom Line: The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold.Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses.This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug.

View Article: PubMed Central - PubMed

Affiliation: Silesian University of Technology, Institute of Automatic Control, Gliwice, Poland.

ABSTRACT
In this work we investigate, by means of a computational stochastic model, how tumor cells with wild-type p53 gene respond to the drug Nutlin, an agent that interferes with the Mdm2-mediated p53 regulation. In particular, we show how the stochastic gene-switching controlled by p53 can explain experimental dose-response curves, i.e., the observed inter-cell variability of the cell viability under Nutlin action. The proposed model describes in some detail the regulation network of p53, including the negative feedback loop mediated by Mdm2 and the positive loop mediated by PTEN, as well as the reversible inhibition of Mdm2 caused by Nutlin binding. The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold. We also performed in silico experiments to evaluate the dose-response curve after a single drug dose delivered in mice, or after its fractionated administration. Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses. This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug.

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Related in: MedlinePlus

Pictorial view of the p53-Mdm2-PTEN interactions in the presence of Nutlin.Black solid arrows: chemical reactions; red solid arrows: chemical reactions involving Nutlin; green dashed arrows: induction of activities; blue solid arrows: translocations. P, phosphate group; u, ubiquitin; n, Nutlin; the symbol  denotes degradation.
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pcbi-1003991-g001: Pictorial view of the p53-Mdm2-PTEN interactions in the presence of Nutlin.Black solid arrows: chemical reactions; red solid arrows: chemical reactions involving Nutlin; green dashed arrows: induction of activities; blue solid arrows: translocations. P, phosphate group; u, ubiquitin; n, Nutlin; the symbol denotes degradation.

Mentions: Roughly speaking, the model of p53 regulation in the absence of Nutlin relies on two feedback loops: a negative loop, coupling p53 with its immediate down-regulator Mdm2, and a positive loop, which involves PTEN, PIP3 and Akt. The existence of the negative feedback assures homeostasis of healthy cells and oscillatory responses of DNA-damaged cells. The positive feedback loop compensate the negative coupling between Mdm2 and p53 by sequestering Mdm2 in cytoplasm. Later on in this section, we will give a more detailed description of these feedbacks. In the model, we distinguish between three physical compartments: the nucleus, the cytoplasm and the extra-cellular space, where, however, only Nutlin is present. In Fig. 1, a diagrammatic representation of the reactions is shown. To mathematically model our complex network, a first possibility is to explicitly model all the reactions as birth-and-death stochastic processes, using the Gillespie algorithm [35] for their simulation. This algorithm is exact for mass action law-based models but it may often be extremely time consuming, even for medium-small networks. This may happen in the presence of two or more largely different timescales, a ubiquitous phenomenon in biology [36]. Here, similarly to the p53/Mdm2/PTEN model under genetic stress proposed in [32], we adopt a hybrid approach, where the process of gene activation-deactivation is stochastic and it is simulated by means of the Gillespie algorithm, whereas the other "fast" reactions are modeled by means of ODEs mostly built on the basis of mass action law. The complete list of model variables is given in S1 Text.


The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise.

Puszynski K, Gandolfi A, d'Onofrio A - PLoS Comput. Biol. (2014)

Pictorial view of the p53-Mdm2-PTEN interactions in the presence of Nutlin.Black solid arrows: chemical reactions; red solid arrows: chemical reactions involving Nutlin; green dashed arrows: induction of activities; blue solid arrows: translocations. P, phosphate group; u, ubiquitin; n, Nutlin; the symbol  denotes degradation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263360&req=5

pcbi-1003991-g001: Pictorial view of the p53-Mdm2-PTEN interactions in the presence of Nutlin.Black solid arrows: chemical reactions; red solid arrows: chemical reactions involving Nutlin; green dashed arrows: induction of activities; blue solid arrows: translocations. P, phosphate group; u, ubiquitin; n, Nutlin; the symbol denotes degradation.
Mentions: Roughly speaking, the model of p53 regulation in the absence of Nutlin relies on two feedback loops: a negative loop, coupling p53 with its immediate down-regulator Mdm2, and a positive loop, which involves PTEN, PIP3 and Akt. The existence of the negative feedback assures homeostasis of healthy cells and oscillatory responses of DNA-damaged cells. The positive feedback loop compensate the negative coupling between Mdm2 and p53 by sequestering Mdm2 in cytoplasm. Later on in this section, we will give a more detailed description of these feedbacks. In the model, we distinguish between three physical compartments: the nucleus, the cytoplasm and the extra-cellular space, where, however, only Nutlin is present. In Fig. 1, a diagrammatic representation of the reactions is shown. To mathematically model our complex network, a first possibility is to explicitly model all the reactions as birth-and-death stochastic processes, using the Gillespie algorithm [35] for their simulation. This algorithm is exact for mass action law-based models but it may often be extremely time consuming, even for medium-small networks. This may happen in the presence of two or more largely different timescales, a ubiquitous phenomenon in biology [36]. Here, similarly to the p53/Mdm2/PTEN model under genetic stress proposed in [32], we adopt a hybrid approach, where the process of gene activation-deactivation is stochastic and it is simulated by means of the Gillespie algorithm, whereas the other "fast" reactions are modeled by means of ODEs mostly built on the basis of mass action law. The complete list of model variables is given in S1 Text.

Bottom Line: The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold.Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses.This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug.

View Article: PubMed Central - PubMed

Affiliation: Silesian University of Technology, Institute of Automatic Control, Gliwice, Poland.

ABSTRACT
In this work we investigate, by means of a computational stochastic model, how tumor cells with wild-type p53 gene respond to the drug Nutlin, an agent that interferes with the Mdm2-mediated p53 regulation. In particular, we show how the stochastic gene-switching controlled by p53 can explain experimental dose-response curves, i.e., the observed inter-cell variability of the cell viability under Nutlin action. The proposed model describes in some detail the regulation network of p53, including the negative feedback loop mediated by Mdm2 and the positive loop mediated by PTEN, as well as the reversible inhibition of Mdm2 caused by Nutlin binding. The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold. We also performed in silico experiments to evaluate the dose-response curve after a single drug dose delivered in mice, or after its fractionated administration. Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses. This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug.

Show MeSH
Related in: MedlinePlus