Intracellular amplifiers of reactive oxygen species affecting mitochondria as radiosensitizers
Radiotherapy (RT) efficacy can be improved by using radiosensitizers, i.e., drugs enhancing the effect of ionizing radiation (IR). One of the side effects of RT includes damage of normal tissue in close proximity to the treated tumor. This problem can be solved by applying cancer specific radiosensi...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2022
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| In: |
Cancers
Year: 2022, Volume: 14, Issue: 1, Pages: 1-19 |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers14010208 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cancers14010208 Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2072-6694/14/1/208 
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| Author Notes: | Hong-Gui Xu, Viktor Reshetnikov, Marit Wondrak, Lisa Eckhardt, Leoni A. Kunz-Schughart, Christina Janko, Rainer Tietze, Christoph Alexiou, Hannes Borchardt, Achim Aigner, Wenjie Gong, Michael Schmitt, Leopold Sellner, Steffen Daum, Hülya Gizem Özkan and Andriy Mokhir |
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| 245 | 1 | 0 | |a Intracellular amplifiers of reactive oxygen species affecting mitochondria as radiosensitizers |c Hong-Gui Xu, Viktor Reshetnikov, Marit Wondrak, Lisa Eckhardt, Leoni A. Kunz-Schughart, Christina Janko, Rainer Tietze, Christoph Alexiou, Hannes Borchardt, Achim Aigner, Wenjie Gong, Michael Schmitt, Leopold Sellner, Steffen Daum, Hülya Gizem Özkan and Andriy Mokhir |
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| 520 | |a Radiotherapy (RT) efficacy can be improved by using radiosensitizers, i.e., drugs enhancing the effect of ionizing radiation (IR). One of the side effects of RT includes damage of normal tissue in close proximity to the treated tumor. This problem can be solved by applying cancer specific radiosensitizers. N-Alkylaminoferrocene-based (NAAF) prodrugs produce reactive oxygen species (ROS) in cancer cells, but not in normal cells. Therefore, they can potentially act as cancer specific radiosensitizers. However, early NAAF prodrugs did not exhibit this property. Since functional mitochondria are important for RT resistance, we assumed that NAAF prodrugs affecting mitochondria in parallel with increasing intracellular ROS can potentially exhibit synergy with RT. We applied sequential Cu+-catalyzed alkyne-azide cycloadditions (CuAAC) to obtain a series of NAAF derivatives with the goal of improving anticancer efficacies over already existing compounds. One of the obtained prodrugs (2c) exhibited high anticancer activity with IC50 values in the range of 5-7.1 µM in human ovarian carcinoma, Burkitt’s lymphoma, pancreatic carcinoma and T-cell leukemia cells retained moderate water solubility and showed cancer specificity. 2c strongly affects mitochondria of cancer cells, leading to the amplification of mitochondrial and total ROS production and thus causing cell death via necrosis and apoptosis. We observed that 2c acts as a radiosensitizer in human head and neck squamous carcinoma cells. This is the first demonstration of a synergy between the radiotherapy and NAAF-based ROS amplifiers. | ||
| 650 | 4 | |a <i>N</i>-alkylaminoferrocene | |
| 650 | 4 | |a cancer | |
| 650 | 4 | |a mitochondrion | |
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| 650 | 4 | |a radiotherapy | |
| 650 | 4 | |a reactive oxygen species | |
| 700 | 1 | |a Reshetnikov, Viktor |e VerfasserIn |4 aut | |
| 700 | 1 | |a Wondrak, Marit |e VerfasserIn |4 aut | |
| 700 | 1 | |a Eckhardt, Lisa |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kunz-Schughart, Leoni A. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Janko, Christina |e VerfasserIn |4 aut | |
| 700 | 1 | |a Tietze, Rainer |e VerfasserIn |4 aut | |
| 700 | 1 | |a Alexiou, Christoph |e VerfasserIn |4 aut | |
| 700 | 1 | |a Borchardt, Hannes |e VerfasserIn |4 aut | |
| 700 | 1 | |a Aigner, Achim |e VerfasserIn |4 aut | |
| 700 | 1 | |a Gong, Wenjie |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Mokhir, Andriy |e VerfasserIn |4 aut | |
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