Related Experiment Video
Updated: Mar 10, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
On p53 revival using system oriented drug dosage design
Muhammad Haseeb1, Shumaila Azam2, A I Bhatti3
1Department of Bioinformatics and Biosciences, Capital University of Science & Technology, Islamabad, Pakistan; Department of Molecular Science and Technology, Ajou University, Suwon, South Korea.
Abstract:
We propose a new paradigm in the drug design for the revival of the p53 pathway in cancer cells. It is shown that the current strategy of using small molecule based Mdm2 inhibitors is not enough to adequately revive p53 in cancerous cells, especially when it comes to the extracting pulsating behavior of p53. This fact has come to notice when a novel method for the drug dosage design is introduced using system oriented concepts. As a test case, small molecule drug Mdm2 repressor Nutlin 3a is considered. The proposed method determines the dose of Nutlin to revive p53 pathway functionality. For this purpose, PBK dynamics of Nutlin have also been integrated with p53 pathway model. The p53 pathway is the focus of researchers for the last thirty years for its pivotal role as a frontline cancer suppressant protein due to its effect on cell cycle checkpoints and cell apoptosis in response to a DNA strand break. That is the reason for finding p53 being absent in more than 50% of tumor cancers. Various drugs have been proposed to revive p53 in cancer cells. Small molecule based drugs are at the foremost and are the subject of advanced clinical trials. The dosage design of these drugs is an important issue. We use control systems concepts to develop the drug dosage so that the cancer cells can be treated in appropriate time. We investigate by using a computational model how p53 protein responds to drug Nutlin 3a, an agent that interferes with the MDM2-mediated p53 regulation. The proposed integrated model describes in some detail the regulation network of p53 including the negative feedback loop mediated by MDM2 and the positive feedback loop mediated by Mdm2 mRNA as well as the reversible represses of MDM2 caused by Nutlin. The reported PBK dynamics of Nutlin 3a are also incorporated to see the full effect. It has been reported that p53 response to stresses in two ways. Either it has a sustained (constant) p53 response, or there are oscillations in p53 concentration. The claimed dosage strategy achieves the p53 response in the first case. However, for the induction of oscillations, it is shown through bifurcation analysis that to achieve oscillating behavior of p53 inhibition of Mdm2 is not enough, rather antirepression of the p53-Mdm2 complex is also needed which leads to the need of a new drug design paradigm.
Insights
Reviving the p53 pathway in cancer cells requires more than Mdm2 inhibitors alone. A new drug design paradigm, incorporating system dynamics and antirepression, is needed for effective p53 pathway restoration and cancer treatment.
Area of Science:
- Oncology
- Systems Biology
- Pharmacology
Background:
- The p53 pathway is crucial for cancer suppression, acting as a tumor suppressor protein that regulates cell cycle checkpoints and apoptosis.
- Over 50% of human cancers exhibit p53 absence, highlighting the need for strategies to restore its function.
- Current small molecule Mdm2 inhibitors show limitations in fully reviving p53 activity, particularly in achieving oscillatory responses.
Purpose of the Study:
- To propose a new paradigm in drug design for reviving the p53 pathway in cancer cells.
- To investigate the efficacy of existing Mdm2 inhibitors and identify limitations in current drug design strategies.
- To develop a novel method for drug dosage design using systems-oriented concepts to optimize p53 pathway functionality.
Main Methods:
- Development of a computational model integrating p53 pathway dynamics with the pharmacokinetics (PBK) of Mdm2 inhibitor Nutlin 3a.
- Application of control systems concepts for designing optimal drug dosage strategies.
- Utilizing bifurcation analysis to explore conditions necessary for achieving sustained versus oscillatory p53 responses.
Main Results:
- The proposed dosage strategy effectively achieves a sustained p53 response.
- Bifurcation analysis reveals that inhibiting Mdm2 alone is insufficient for inducing p53 oscillations.
- Antirepression of the p53-Mdm2 complex is identified as a necessary factor for achieving oscillatory p53 behavior.
Conclusions:
- Current Mdm2 inhibitor strategies are inadequate for fully restoring p53 pathway functionality, especially for achieving pulsatile responses.
- A new drug design paradigm is required, potentially involving antirepression mechanisms, to effectively revive the p53 pathway in cancer cells.
- Systems-oriented approaches and advanced modeling are essential for optimizing cancer drug dosage and therapeutic outcomes.
Related Concept Videos
01:28Dosage Regimens: Designs and Approaches
01:24Dosage Regimen: Individualization
01:24Rational Dosage Regimen: Maintenance Dose and Loading Dose
In most cases, drugs are administered repetitively or infused continuously to maintain a steady-state concentration in the body. At a steady...
01:24Drug Toxicity: Dose-Dependent Reactions
01:01Dosage Regimen: Fixed Dose
Fixed-dose regimens can be used for various routes of administration, including intravenous (IV) injections and oral medications. For IV administration, a predetermined amount of the drug is...
01:01Dosage Regimens: Partial Pharmacokinetic Parameters