ArticlePLoS computational biology2014
The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise.
Article in PLoS computational biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 39 citations in OpenAlex.
- Review
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- Mathematical Modelling of p53 Signalling during DNA Damage Response: A Survey.International journal of molecular sciences · 2021Review
- Double Empirical Bayes Testing.International statistical review = Revue internationale de statistique · 2020Article
- Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression.Biomolecules · 2020Review
- Model-based optimization of combination protocols for irradiation-insensitive cancers.Scientific reports · 2020Article
- Phenotypic selection through cell death: stochastic modelling of O-6-methylguanine-DNA methyltransferase dynamics.Royal Society open science · 2020Article
- Article
- Sliding mode controller-observer pair for p53 pathway.IET systems biology · 2019Article
- System-based strategies for p53 recovery.IET systems biology · 2018Article
- Promoter Hypermethylation of the ATM Gene as a Novel Biomarker for Breast CancerAsian Pacific journal of cancer prevention : APJCP · 2017Article
- Influence of parameter perturbations on the reachability of therapeutic target in systems with switchings.Biomedical engineering online · 2017Article
- The role of stochastic gene switching in determining the pharmacodynamics of certain drugs: basic mechanisms.Journal of pharmacokinetics and pharmacodynamics · 2016Article
- Gene switching rate determines response to extrinsic perturbations in the self-activation transcriptional network motif.Scientific reports · 2016Article
- Feedbacks, Bifurcations, and Cell Fate Decision-Making in the p53 System.PLoS computational biology · 2016Article
- Correction: The pharmacodynamics of the p53-Mdm2 targeting drug nutlin: the role of gene-switching noise.PLoS computational biology · 2015Article
Corrections and comments
- Erratum issued
Authors and funding
3 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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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