Single-Cell Kinetic Modeling of β-Lapachone Metabolism in Head and Neck Squamous Cell Carcinoma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ordinary Differential Equation Model Construction
2.2. Sensitivity Analysis
2.3. Single-Cell RNA Sequencing Data Analysis
3. Results
3.1. A Systems-Level Model of Superoxide and H2O2 Generation by Quinone Cycling
- (1)
- sets of critical H2O2-stabilizing antioxidant systems;
- (2)
- metabolism of the xenobiotic drug β-lapachone;
- (3)
- the permeation of key species across membranes of the cell, including organelle-specific transport.
3.2. Head and Neck Squamous Cell Carcinoma Cells Exhibit Heterogeneity of Redox Gene Expression
3.3. Initializing Single-Cell ODE Models with scRNA-Seq
3.4. Sensitivity Analysis Shows H2O2 Production Is Insensitive to Individual Enzymatic Parameters
3.5. Comparison of H2O2 Accumulation in Healthy and Cancer Cells Identifies Patients with Greatest Potential for Targeted Therapy
3.6. Initializing Single-Cell ODE Models with Patient HNSCC Scrna-Seq Identifies Proteins Correlated with NADPH Ratio
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Reaction Name | Rate Term |
---|---|
β-lap permeation * | k34 * Acells * ([β-lapext]–[β-lapQ]) |
β-lap reduction | k29 * [β-lapQ] * [NADPH] |
β-lap semioxidation | k30 * [β-lapHQ] * [O2] |
β-lap oxidation | k31 * [β-lapSQ] * [O2] |
superoxide dismutase | k32 * [O2•−]2 |
β-lap semireduction | k33 * [β-lapQ] * [NADPH] |
β-lap semiquinone semireduction | k33 * [β-lapSQ] * [NADPH] |
β-lap glutathionylation | k35 * [β-lapHQ] * [GSH] |
Glutathionylated β-lap permeation * | k36 * Acells * [β-lapHQ-SG] |
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Raddatz, A.D.; Furdui, C.M.; Bey, E.A.; Kemp, M.L. Single-Cell Kinetic Modeling of β-Lapachone Metabolism in Head and Neck Squamous Cell Carcinoma. Antioxidants 2023, 12, 741. https://doi.org/10.3390/antiox12030741
Raddatz AD, Furdui CM, Bey EA, Kemp ML. Single-Cell Kinetic Modeling of β-Lapachone Metabolism in Head and Neck Squamous Cell Carcinoma. Antioxidants. 2023; 12(3):741. https://doi.org/10.3390/antiox12030741
Chicago/Turabian StyleRaddatz, Andrew D., Cristina M. Furdui, Erik A. Bey, and Melissa L. Kemp. 2023. "Single-Cell Kinetic Modeling of β-Lapachone Metabolism in Head and Neck Squamous Cell Carcinoma" Antioxidants 12, no. 3: 741. https://doi.org/10.3390/antiox12030741