Intracellular amplifiers of reactive oxygen species affecting mitochondria as radiosensitizers

Xu H, 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 H, Mokhir A (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Cancers MDPI

Book Volume: 14

Article Number: 208

Journal Issue: 1

DOI: 10.3390/cancers14010208

Abstract

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 com-pounds. 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.

Authors with CRIS profile

Honggui Xu Lehrstuhl für Organische Chemie II Viktor Reshetnikov Lehrstuhl für Organische Chemie II Christina Janko Department of Otorhinolaryngology – Head and Neck Surgery Rainer Tietze Department of Otorhinolaryngology – Head and Neck Surgery Christoph Alexiou Professur für Nanomedizin Steffen Daum Lehrstuhl für Organische Chemie II Hülya Özkan Lehrstuhl für Organische Chemie II Andriy Mokhir Professur für Organische Chemie

Involved external institutions

Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE) Universität Leipzig DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE)

How to cite

APA:

Xu, H., Reshetnikov, V., Wondrak, M., Eckhardt, L., Kunz-Schughart, L.A., Janko, C.,... Mokhir, A. (2022). Intracellular amplifiers of reactive oxygen species affecting mitochondria as radiosensitizers. Cancers, 14(1). https://dx.doi.org/10.3390/cancers14010208

MLA:

Xu, Honggui, et al. "Intracellular amplifiers of reactive oxygen species affecting mitochondria as radiosensitizers." Cancers 14.1 (2022).

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