Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. General
2.2. Synthesis of Prodrugs and Their Characterization in Cell Free Settings
2.3. Cells, Cell Culture and Cellular Assays
3. Results and Discussion
3.1. Possible Reasons of Poor Anticancer Activity of Drug 1
3.2. Design, Synthesis and Characterization of the Prodrugs
3.3. Stability and Solubility of Prodrugs 2a–2d in the Aqueous Neutral Solution and Their Lipophilicity
3.4. Generation of ROS in the Presence of the Prodrugs in Cell Free Settings
3.5. Anticancer Activity of the Prodrugs towards Different Cell Lines
3.6. The Mechanism of the Anticancer Activity of Prodrug 2c
3.7. An Active Form of Prodrug 2c in Cells and the Role of Nitric Oxide in the Anticancer Activity of 2c
3.8. Evaluation of Cancer Cell Specificity of the Prodrug 2c
3.9. Synergy of the NAAF-Prodrugs with Radiotherapy
4. 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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Prodrug | logP (Prodrug/Hydrolyzed Prodrug) i | Solubility ii | ROS Release Efficacy iv |
---|---|---|---|
1 | 4.87 ± 0.05/2.83 ± 0.07 | 67 ± 5 iii | 0.99 ± 0.16 |
2a | 5.27 ± 0.10/2.92 ± 0.14 | 100 (30) | 0.74 ± 0.19 |
2b | 5.37 ± 0.10/3.10 ± 0.12 | 100 (30) | 0.76 ± 0.19 |
2c | 5.37 ± 0.15/3.23 ± 0.11 | 30 (10) | 0.35 ± 0.17 |
2c_c | 3.90 ± 0.08 | 55 ± 5 | 0.050 ± 0.003 |
2d | 5.56 ± 0.14/3.42 ± 0.14 | 30 (10) | 0.37 ± 0.13 |
Prodrug/Control | IC50 (μM)/Human Cancer Cell Lines i | |||
---|---|---|---|---|
A2780 | BL-2 | AsPC1 | Jurkat | |
1 | 30 ± 5 | 17 ± 6 | - | 30 ± 4 |
2c | 4.0 ± 0.5 | 5.7 ± 2.7 | 7.1 ± 1.0 | 5 ± 2 |
2c_c | 6.1 ± 1.5 | - | - | - |
5b | 7 ± 2 | 5 ± 3 | 6.7 ± 0.5 | 7.2 ± 0.1 |
6 | >100 | >100 | - | >100 |
Prodrug | Concentration (µM) | Radiosensitization i | p-Values ii | |
---|---|---|---|---|
SAS | FaDu | |||
2c | 10 | +/− | <0.001 | ns |
25 | + | <0.001 | <0.001 | |
5b | 1 | + | <0.001 | <0.01 |
2.5 | + | <0.001 | <0.001 | |
6 | 25 | - | ns | ns |
7 | 0.1 | +/− | ns | <0.01 |
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Xu, H.-G.; Reshetnikov, V.; Wondrak, M.; Eckhardt, L.; Kunz-Schughart, L.A.; Janko, C.; Tietze, R.; Alexiou, C.; Borchardt, H.; Aigner, A.; et al. Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers. Cancers 2022, 14, 208. https://doi.org/10.3390/cancers14010208
Xu H-G, Reshetnikov V, Wondrak M, Eckhardt L, Kunz-Schughart LA, Janko C, Tietze R, Alexiou C, Borchardt H, Aigner A, et al. Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers. Cancers. 2022; 14(1):208. https://doi.org/10.3390/cancers14010208
Chicago/Turabian StyleXu, Hong-Gui, Viktor Reshetnikov, Marit Wondrak, Lisa Eckhardt, Leoni A. Kunz-Schughart, Christina Janko, Rainer Tietze, Christoph Alexiou, Hannes Borchardt, Achim Aigner, and et al. 2022. "Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers" Cancers 14, no. 1: 208. https://doi.org/10.3390/cancers14010208
APA StyleXu, H.-G., Reshetnikov, V., Wondrak, M., Eckhardt, L., Kunz-Schughart, L. A., Janko, C., Tietze, R., Alexiou, C., Borchardt, H., Aigner, A., Gong, W., Schmitt, M., Sellner, L., Daum, S., Özkan, H. G., & Mokhir, A. (2022). Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers. Cancers, 14(1), 208. https://doi.org/10.3390/cancers14010208