Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Lines and Culture
2.2. Antibodies
2.3. Reagents and Chemicals
2.4. Relative Survival Assays (DNA Assay)
2.5. O2 Consumption Rate (OCR) and Extracellular Acidification Rates (ECAR) Assessments
2.6. Western Blotting
2.7. H2O2, ATP, and NAD+ Quantification
2.8. Immunofluorescence Assay
2.9. Alkaline Comet Assay
2.10. Caspase Activity Assay for Apoptosis Detection
2.11. Annexin-V FITC/PI Assay
2.12. In Vivo Antitumor Efficacy and Pharmacokinetic (PK) and Pharmacodynamic (PD) Studies
2.13. Statistical Analysis
3. Results
3.1. IP-DNQ Exerts Potent Cytotoxicity in Various Types of NQO1+ Cancer Cells
3.2. IP-DNQ Induces NQO1-Dependent ROS Formation, PARP1 Hyperactivation, and NAD+/ATP Loss
3.3. IP-DNQ Induces NQO1-Dependent DNA Damage, and Ca2+ Plays a Pivotal Role in IP-DNQ-Induced Cytotoxicity
3.4. IP-DNQ Initiates Both Apoptosis and Programmed Necrosis in NQO1+ Cancer Cells
3.5. Antitumor Efficacy of IP-DNQ in Orthotopic NSCLC Xenografts, Pharmacokinetics (PK) and Tissue Pharmacodynamics (PD)
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Wang, J.; Su, X.; Jiang, L.; Boudreau, M.W.; Chatkewitz, L.E.; Kilgore, J.A.; Zahid, K.R.; Williams, N.S.; Chen, Y.; Liu, S.; et al. Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms. Cancers 2023, 15, 5844. https://doi.org/10.3390/cancers15245844
Wang J, Su X, Jiang L, Boudreau MW, Chatkewitz LE, Kilgore JA, Zahid KR, Williams NS, Chen Y, Liu S, et al. Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms. Cancers. 2023; 15(24):5844. https://doi.org/10.3390/cancers15245844
Chicago/Turabian StyleWang, Jiangwei, Xiaolin Su, Lingxiang Jiang, Matthew W. Boudreau, Lindsay E. Chatkewitz, Jessica A. Kilgore, Kashif Rafiq Zahid, Noelle S. Williams, Yaomin Chen, Shaohui Liu, and et al. 2023. "Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms" Cancers 15, no. 24: 5844. https://doi.org/10.3390/cancers15245844
APA StyleWang, J., Su, X., Jiang, L., Boudreau, M. W., Chatkewitz, L. E., Kilgore, J. A., Zahid, K. R., Williams, N. S., Chen, Y., Liu, S., Hergenrother, P. J., & Huang, X. (2023). Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms. Cancers, 15(24), 5844. https://doi.org/10.3390/cancers15245844