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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

Time-courses of the total (green) and free (red) intracellular Nutlin in response to two different Nutlin extra-cellular concentrations in RKO (left column) and SJSA-1 (right column) cells.Extra-cellular concentrations: panels A and C, M; panels B and D, M. Solid lines represent medians, and dotted lines first and third quartiles. The PTEN feedback loop is active.
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pcbi-1003991-g004: Time-courses of the total (green) and free (red) intracellular Nutlin in response to two different Nutlin extra-cellular concentrations in RKO (left column) and SJSA-1 (right column) cells.Extra-cellular concentrations: panels A and C, M; panels B and D, M. Solid lines represent medians, and dotted lines first and third quartiles. The PTEN feedback loop is active.

Mentions: We also predicted the cell response when the PTEN feedback was disabled (keeping all the other parameters unchanged), to mimic tumor cells in which PTEN is not expressed. The expected reduction of Nutlin efficacy occurs only when no amplification of Mdm2 is present, when , instead, the effect of PTEN deletion is very limited. It is interesting to compare the dynamics of nuclear-phosphorylated p53 and nuclear-phosphorylated Mdm2 after the exposure to different Nutlin concentrations among those of Fig 2. In Fig. 3, we show stochastic simulations of RKO cells for the exposure to total concentrations of M and M (panels A–D). The median number of p53 molecules grows after the start of Nutlin exposure and tends to stabilize after some oscillations to a value higher than the baseline value. When the PTEN feedback is disabled, the increase of p53 amount is reduced. In the panels E–H of Fig. 3, showing the simulation of SJSA-1 cells, we may note that the number of nuclear Mdm2 molecules is larger than in the case of RKO cells, and the number of p53 molecules is smaller, in agreement with the presence of a robust Mdm2 gene amplification. Fig. 4 shows the corresponding dynamics of total and free intra-cellular Nutlin. We recall here that molecules in a cell of volume equal to m3 correspond to a concentration of M. Note that most of the intra-cellular Nutlin is bound to the Mdm2 molecules.


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)

Time-courses of the total (green) and free (red) intracellular Nutlin in response to two different Nutlin extra-cellular concentrations in RKO (left column) and SJSA-1 (right column) cells.Extra-cellular concentrations: panels A and C, M; panels B and D, M. Solid lines represent medians, and dotted lines first and third quartiles. The PTEN feedback loop is active.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003991-g004: Time-courses of the total (green) and free (red) intracellular Nutlin in response to two different Nutlin extra-cellular concentrations in RKO (left column) and SJSA-1 (right column) cells.Extra-cellular concentrations: panels A and C, M; panels B and D, M. Solid lines represent medians, and dotted lines first and third quartiles. The PTEN feedback loop is active.
Mentions: We also predicted the cell response when the PTEN feedback was disabled (keeping all the other parameters unchanged), to mimic tumor cells in which PTEN is not expressed. The expected reduction of Nutlin efficacy occurs only when no amplification of Mdm2 is present, when , instead, the effect of PTEN deletion is very limited. It is interesting to compare the dynamics of nuclear-phosphorylated p53 and nuclear-phosphorylated Mdm2 after the exposure to different Nutlin concentrations among those of Fig 2. In Fig. 3, we show stochastic simulations of RKO cells for the exposure to total concentrations of M and M (panels A–D). The median number of p53 molecules grows after the start of Nutlin exposure and tends to stabilize after some oscillations to a value higher than the baseline value. When the PTEN feedback is disabled, the increase of p53 amount is reduced. In the panels E–H of Fig. 3, showing the simulation of SJSA-1 cells, we may note that the number of nuclear Mdm2 molecules is larger than in the case of RKO cells, and the number of p53 molecules is smaller, in agreement with the presence of a robust Mdm2 gene amplification. Fig. 4 shows the corresponding dynamics of total and free intra-cellular Nutlin. We recall here that molecules in a cell of volume equal to m3 correspond to a concentration of M. Note that most of the intra-cellular Nutlin is bound to the Mdm2 molecules.

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