title: On p53 revival using system oriented drug dosage design.
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.
authors.affiliation: Department of Bioinformatics and Biosciences, Capital University of Science & Technology, Islamabad, Pakistan; Department of Molecular Science and Technology, Ajou University, Suwon, South Korea. Electronic address: haseeb3389@hotmail.com.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Haseeb
authors.affiliation: Department of Bioinformatics and Biosciences, Capital University of Science & Technology, Islamabad, Pakistan.
authors.forename: Shumaila
authors.initials: S
authors.lastname: Azam
authors.affiliation: CASPR, Department of Electronics Engineering, Capital University of Science & Technology, Islamabad, Pakistan. Electronic address: aamer987@gmail.com.
authors.forename: A I
authors.initials: AI
authors.lastname: Bhatti
authors.affiliation: CASPR, Department of Electronics Engineering, Capital University of Science & Technology, Islamabad, Pakistan.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Azam
authors.affiliation: Department of Electrical Engineering, National University of Computer & Emerging Sciences, Islamabad, Pakistan.
authors.forename: Mukhtar
authors.initials: M
authors.lastname: Ullah
authors.affiliation: Department of Bioinformatics and Biosciences, Capital University of Science & Technology, Islamabad, Pakistan.
authors.forename: Sahar
authors.initials: S
authors.lastname: Fazal
mesh_terms: D019295:Computational Biology / Q000379:methods; D015195:Drug Design; D054796:Drug Dosage Calculations; D005246:Feedback; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Cancer; Mdm2; Nutlin; PBK; p53