Abstract
Simple SummaryProdrugs 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.
Highlights
Radiotherapy (RT) using ionizing radiation (IR) is a common approach for the treatment of cancer [1,2]
To understand why prodrug 1 exhibits weak anticancer activity, we investigated its basic properties in cell free settings
We observed that 1 reacts quickly with H2O2 in cell free settings, under formation of the corresponding NAAF, which catalyzes the generation of HO from H2O2
Summary
Radiotherapy (RT) using ionizing radiation (IR) is a common approach for the treatment of cancer [1,2]. An alternative approach is based on the IR potentiation by drugs increasing intracellular levels of reactive oxygen species (ROS), e.g., sorafenib [9], L-S-buthionine (BSO) [10], As2O3 [11], diisopropylamine dichloroacetate (DADA) [12] and ferrocene derivatives [13,14]. Despite their high antitumor efficacy, these drugs affect healthy tissues and cells, which so far precludes potential clinical applications of RT approaches based on ROS-regulation. We have previously demonstrated that prodrug 1 (Figure 1) and its fluorogenic derivatives moderately affect mitochondria of cancer cells [25,28], their anticancer efficacy is very low [25]
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