ArticleThe Journal of pharmacology and experimental therapeutics2015
Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells.
Article in The Journal of pharmacology and experimental therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 30 citations in OpenAlex.
- Population-based meta-analysis of bortezomib exposure-response relationships in multiple myeloma patients.Journal of pharmacokinetics and pharmacodynamics · 2020Pooled it
- Personalized Boolean network dynamic profiling and machine learning approaches to identify combinatorial treatments for prostate cancer.Frontiers in pharmacology · 2026Article
- Mathematical Modeling of Neuroinflammation in Neurodegenerative Diseases.CPT: pharmacometrics & systems pharmacology · 2025Review
- Data-driven inference of Boolean networks from transcriptomes to predict cellular differentiation and reprogramming.NPJ systems biology and applications · 2025Article
- Logic-based modeling of inflammatory macrophage cross talk with glomerular endothelial cells in diabetic kidney disease.American journal of physiology. Renal physiology · 2025Article
- Systems Pharmacodynamic Model of Combined Gemcitabine and Trabectedin in Pancreatic Cancer Cells. Part I: Effects on Signal Transduction Pathways Related to Tumor GrowthJournal of pharmaceutical sciences · 2024Article
- Normalizing Input-Output Relationships of Cancer Networks for Reversion Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Experimental and computational assessment of the synergistic pharmacodynamic drug-drug interactions of a triple combination therapy in refractory HER2-positive breast cancer cells.Journal of pharmacokinetics and pharmacodynamics · 2022Article
- Editor's note on the themed issue: integration of machine learning and quantitative systems pharmacology.Journal of pharmacokinetics and pharmacodynamics · 2022Article
- Network-Based Systems Analysis Explains Sequence-Dependent Synergism of Bortezomib and Vorinostat in Multiple Myeloma.The AAPS journal · 2021Article
- Alpha-lipoic acid alters the antitumor effect of bortezomib in melanoma cells in vitro.Scientific reports · 2020Article
- Pharmacodynamic Drug-Drug Interactions.Clinical pharmacology and therapeutics · 2019Review
- Pharmacodynamic Models of Differential Bortezomib Signaling Across Several Cell Lines of Multiple Myeloma.CPT: pharmacometrics & systems pharmacology · 2019Article
- Discrete dynamic network modeling of oncogenic signaling: Mechanistic insights for personalized treatment of cancer.Current opinion in systems biology · 2018Review
- Systems pharmacological analysis of mitochondrial cardiotoxicity induced by selected tyrosine kinase inhibitors.Journal of pharmacokinetics and pharmacodynamics · 2018Article
- Network-Based Analysis of Bortezomib Pharmacodynamic Heterogeneity in Multiple Myeloma Cells.The Journal of pharmacology and experimental therapeutics · 2018Article
- Boolean network modeling in systems pharmacology.Journal of pharmacokinetics and pharmacodynamics · 2018Review
- Cell Signaling Model Connects Vorinostat Pharmacokinetics and Tumor Growth Response in Multiple Myeloma Xenografts.CPT: pharmacometrics & systems pharmacology · 2017Article
- A Six-Stage Workflow for Robust Application of Systems Pharmacology.CPT: pharmacometrics & systems pharmacology · 2016Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Systems models of biological networks show promise for informing drug target selection/qualification, identifying lead compounds and factors regulating disease progression, rationalizing combinatorial regimens, and explaining sources of intersubject variability and adverse drug reactions. However, most models of biological systems are qualitative and are not easily coupled with dynamical models of drug exposure-response relationships. In this proof-of-concept study, logic-based modeling of signal transduction pathways in U266 multiple myeloma (MM) cells is used to guide the development of a simple dynamical model linking bortezomib exposure to cellular outcomes. Bortezomib is a commonly used first-line agent in MM treatment; however, knowledge of the signal transduction pathways regulating bortezomib-mediated cell cytotoxicity is incomplete. A Boolean network model of 66 nodes was constructed that includes major survival and apoptotic pathways and was updated using responses to several chemical probes. Simulated responses to bortezomib were in good agreement with experimental data, and a reduction algorithm was used to identify key signaling proteins. Bortezomib-mediated apoptosis was not associated with suppression of nuclear factor κB (NFκB) protein inhibition in this cell line, which contradicts a major hypothesis of bortezomib pharmacodynamics. A pharmacodynamic model was developed that included three critical proteins (phospho-NFκB, BclxL, and cleaved poly (ADP ribose) polymerase). Model-fitted protein dynamics and cell proliferation profiles agreed with experimental data, and the model-predicted IC50 (3.5 nM) is comparable to the experimental value (1.5 nM). The cell-based pharmacodynamic model successfully links bortezomib exposure to MM cellular proliferation via protein dynamics, and this model may show utility in exploring bortezomib-based combination regimens.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.