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Antioxid Redox Signal. 2018 Oct 1;29(10):937-952. doi: 10.1089/ars.2017.7048. Epub 2017 Sep 14.

Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma.

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1 The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University , Atlanta, Georgia .
2 School of Chemical and Biomolecular Engineering, Georgia Institute of Technology , Atlanta, Georgia .
3 Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine , Winston-Salem, North Carolina.
4 Department of Pharmacology, University of Texas Southwestern Medical Center , Dallas, Texas.



The purpose of this study was to investigate differential nicotinamide adenine dinucleotide phosphate, reduced (NADPH) production between radiation-sensitive and -resistant head and neck squamous cell carcinoma (HNSCC) cell lines and whether these differences are predictive of sensitivity to the chemotherapeutic β-lapachone.


We have developed a novel human genome-scale metabolic modeling platform that combines transcriptomic, kinetic, thermodynamic, and metabolite concentration data. Upon incorporation of this information into cell line-specific models, we observed that the radiation-resistant HNSCC model redistributed flux through several major NADPH-producing reactions. Upon RNA interference of canonical NADPH-producing genes, the metabolic network can further reroute flux through alternate NADPH biosynthesis pathways in a cell line-specific manner. Model predictions of perturbations in cellular NADPH production after gene knockdown match well with experimentally verified effects of β-lapachone treatment on NADPH/NADP+ ratio and cell viability. This computational approach accurately predicts HNSCC-specific oxidoreductase genes that differentially affect cell viability between radiation-responsive and radiation-resistant cancer cells upon β-lapachone treatment.


Quantitative genome-scale metabolic models that incorporate multiple levels of biological data are applied to provide accurate predictions of responses to a NADPH-dependent redox cycling chemotherapeutic drug under a variety of perturbations.


Our modeling approach suggests differences in metabolism and β-lapachone redox cycling that underlie phenotypic differences in radiation-sensitive and -resistant cancer cells. This approach can be extended to investigate the synergistic action of NAD(P)H: quinone oxidoreductase 1 bioactivatable drugs and radiation therapy. Antioxid. Redox Signal. 29, 937-952.


NADPH; flux balance analysis; head and neck cancer; redox cycling; β-lapachone

[Available on 2019-10-01]

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