Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers

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 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.

A concept of dual-responsive prodrugs based on oligomerization-controlled reactivity of ester groups: an improvement of cancer cells versus neutrophils selectivity of camptothecin

“… 22 We tested this hypothesis in two representative cell lines, SAS and FaDu, which are cancer models established in our laboratory for exploring synergistic effects between IR and new drugs. 22 …”

“…Since ionizing irradiation (IR) increases ROS in cells, 21 we assumed that it could also facilitate the prodrug activation. 22 We tested this hypothesis in two representative cell lines, SAS and FaDu, which are cancer models established in our laboratory for exploring synergistic effects between IR and new drugs. 22 First, we confirmed that the prodrug inhibits growth of both SAS (IC 50 = 4 ± 2 μM) and FaDu cells (IC 50 = 8 ± 2 μM) at 48 h incubation time.…”

“…22 We tested this hypothesis in two representative cell lines, SAS and FaDu, which are cancer models established in our laboratory for exploring synergistic effects between IR and new drugs. 22 First, we confirmed that the prodrug inhibits growth of both SAS (IC 50 = 4 ± 2 μM) and FaDu cells (IC 50 = 8 ± 2 μM) at 48 h incubation time. At the concentration of 0.5 μM (but not 0.2 μM) it also inhibits the capacity of these cells to form colonies (p < 0.01).…”

A prodrug activated by H2O2 and mitochondrial hydroxide: an improvement of cancer cells versus neutrophils selectivity

“…Since ionizing irradiation (IR) increases ROS in cells, [21] we assumed that it could also facilitate the prodrug activation. [22] We tested this hypothesis in two representative cell lines, SAS and FaDu, which are cancer models established in our laboratory for exploring synergistic effects between IR and new drugs. [22] First, we confirmed that the prodrug inhibits growth of both SAS (IC50= 4  2 M) and FaDu cells (IC50= 8  2 M) at 48 h incubation time.…”

“…[22] We tested this hypothesis in two representative cell lines, SAS and FaDu, which are cancer models established in our laboratory for exploring synergistic effects between IR and new drugs. [22] First, we confirmed that the prodrug inhibits growth of both SAS (IC50= 4  2 M) and FaDu cells (IC50= 8  2 M) at 48 h incubation time. At the concentration of 0.5 M (but not 0.2 M) it also inhibits the capacity of these cells to form colonies (p< 0.01).…”