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Article

Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers

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Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany
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OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden—Rossendorf, 01307 Dresden, Germany
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National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany
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Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Universitätsklinikum Erlangen, 91054 Erlangen, Germany
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Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, Leipzig University, 04107 Leipzig, Germany
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Department of Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany
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Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
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Takeda Pharmaceuticals, Cambridge, MA 02139, USA
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Merck, Im Laternenacker 5, 8200 Schaffhausen, Switzerland
*
Author to whom correspondence should be addressed.
Academic Editors: Alexandros G. Georgakilas and Alfonso Urbanucci
Cancers 2022, 14(1), 208; https://doi.org/10.3390/cancers14010208
Received: 15 December 2021 / Revised: 27 December 2021 / Accepted: 29 December 2021 / Published: 31 December 2021
Prodrugs that increase the level of reactive oxygen species (ROS) specifically in cancer cells while not affecting normal cells can potentially act as radiosensitizers for side effect free radiotherapy (RT). However, previously known ROS-amplifying prodrugs were found to not beuseful for this purpose. Since functional mitochondria are necessary for RT-resistance, we assumed that the problem could be solved by using dual prodrugs as radiosensitizers, both targeting mitochondria and simultaneously inducing ROS. In this paper, we explored this possibility. In particular, we developed an N-alkylaminoferrocene-based prodrug (2c) effective at low μMolar concentrations. Upon conversion to its active form 2c_BA in aqueous solution, it is efficiently taken up by cancer cells. This leads to the decrease of their mitochondrial membrane potential and the amplification of both, intracellular mitochondrial and total ROS generation. We found that 2c_BA acts as an efficient radiosensitizer in human head and neck squamous carcinoma cells in vitro.
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. View Full-Text
Keywords: N-alkylaminoferrocene; cancer; mitochondrion; reactive oxygen species; prodrug; radiotherapy N-alkylaminoferrocene; cancer; mitochondrion; reactive oxygen species; prodrug; radiotherapy
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MDPI and ACS Style

Xu, 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. Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers. Cancers 2022, 14, 208. https://doi.org/10.3390/cancers14010208

AMA Style

Xu H-G, Reshetnikov V, Wondrak M, Eckhardt L, Kunz-Schughart LA, Janko C, Tietze R, Alexiou C, Borchardt H, Aigner A, Gong W, Schmitt M, Sellner L, Daum S, Özkan HG, Mokhir A. Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers. Cancers. 2022; 14(1):208. https://doi.org/10.3390/cancers14010208

Chicago/Turabian Style

Xu, Hong-Gui, 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 G. Özkan, and Andriy Mokhir. 2022. "Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers" Cancers 14, no. 1: 208. https://doi.org/10.3390/cancers14010208

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