Novel Synthetic SOD/Catalase Mimetics Can Mitigate Capillary Endothelial Cell Apoptosis Caused by Ionizing Radiation

Abstract

Numerous in vitro and in vivo studies have shown that the endothelial cells of the microvasculature of the lung and kidney are damaged by exposure to ionizing radiation, and this sustained endothelial cell injury is involved in the early and late radiation effects observed in these tissues. It is well accepted that ionizing radiation causes the generation of reactive oxygen species during exposure that results in damage to DNA and cellular organelles. It is more controversial, however, whether additional biochemical events or long-lived radicals occur and persist postirradiation that amplify and initiate new forms of cellular damage. Two families of Eukarion (EUK) compounds have been synthesized that possess superoxide dismutase (SOD), catalase and peroxidase activities. The Mn porphyrins are available orally whereas the salen Mn complexes are administered by injection. In the present study we have examined the ability of these SOD/catalase mimetics to prevent apoptosis of endothelial cells when administered 1 h postirradiation (mitigation). A range of salen Mn complex (EUK-189 and EUK-207) and Mn porphyrins (EUK-418, -423, -425, -450, -451, -452, -453) were used to treat endothelial cells 1 h after the cells received 2–20 Gy ionizing radiation in vitro. Two lead compounds, EUK-207 at a dose of 30 μM and EUK-451 at a dose of 10 μM, exhibited low toxicity and mitigated radiation-induced apoptosis. Future animal studies will test whether these compounds protect when administered after radiation exposure as would be done after a radiological accident or a terrorism event.

Superoxide Dismutase Mimics

“…Unlike Dr. Batinić-Haberle, we believe that SOD activity is not as important as other properties, such as catalase and other reactive oxygen species or reactive nitrogen species scavenging properties, lipophilicity, lack of toxicity, or intracellular stability, in determining biological efficacy (discussed in our article) (2). Our position is further supported by our finding that these neutral Mn porphyrins are potently antiapoptotic in two cellular injury models (2,4), an important point that Dr. Batinić-Haberle et al fail to mention.…”

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

“…9). While the exact mechanisms by which therapeutically applied MSCs as well as the SOD-mimetic EU134 prevent vascular cell loss are not known, their ability to reduce radiation-induced apoptosis in capillary EC cultures may be relevant as they result in improved clonogenic EC survival as shown here and by others (21,79). In addition to a direct protective effect on the lung endothelium, proper vascular function and restoration of SOD1 expression may contribute to a microenvironment, for example, through normalization of immune cell infiltration, which favors both prevention of and recovery from radiation injury to vascular and other resident lung cells.…”

Mitigation of Radiation-Induced Lung Injury with EUK-207 and Genistein: Effects in Adolescent Rats

“…We compared genistein treatment to similar treatment with the antioxidant EUK-207, a salen-manganese superoxide dismutase (SOD)-catalase mimetic (19, 20) and examined how effectively damage to the lung can be mitigated by administration of the drugs when initiated at later times after radiation exposure. Both of these agents have been reported to scavenge reactive oxygen species and to reduce activity of the NFkB pathway (19–29) and are well-tolerated, suggesting low toxicity.…”