Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers.
Hong-Gui XuViktor ReshetnikovMarit WondrakLisa EckhardtLeoni A Kunz-SchughartChristina JankoRainer TietzeChristoph AlexiouHannes BorchardtAchim AignerWenjie GongMichael SchmittLeopold SellnerSteffen DaumHülya Gizem ÖzkanAndriy MokhirPublished in: Cancers (2021)
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 IC 50 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.
Keyphrases
- reactive oxygen species
- cell death
- cell cycle arrest
- papillary thyroid
- induced apoptosis
- endothelial cells
- oxidative stress
- squamous cell
- early stage
- radiation therapy
- endoplasmic reticulum stress
- radiation induced
- signaling pathway
- lymph node metastasis
- high intensity
- squamous cell carcinoma
- locally advanced
- diffuse large b cell lymphoma
- bone marrow
- low grade
- room temperature
- nucleic acid