High throughput screen of small molecules as potential countermeasures to galactic cosmic radiation induced cellular dysfunction

Abstract

Space travel increases galactic cosmic ray exposure to flight crews and this is significantly elevated once travel moves beyond low Earth orbit. This includes combinations of high energy protons and heavy ions such as 56Fe or 16O. There are distinct differences in the biological response to low-energy transfer (x-rays) or high-energy transfer (High-LET). However, given the relatively low fluence rate of exposure during flight operations, it might be possible to manage these deleterious effects using small molecules currently available. Virtually all reports to date examining small molecule management of radiation exposure are based on low-LET challenges. To that end an FDA approved drug library (725 drugs) was used to perform a high throughput screen of cultured cells following exposure to galactic cosmic radiation. The H9c2 myoblasts, ES-D3 pluripotent cells, and Hy926 endothelial cell lines were exposed to a single exposure (75 cGy) using the 5-ion GCRsim protocol developed at the NASA Space Radiation Laboratory (NSRL). Following GCR exposure cells were maintained for up to two weeks. For each drug (@10µM), a hierarchical cumulative score was developed incorporating measures of mitochondrial and cellular function, oxidant stress and cell senescence. The top 160 scores were retested following a similar protocol using 1µM of each drug. Within the 160 drugs, 33 are considered to have an anti-inflammatory capacity, while others also indirectly suppressed pro-inflammatory pathways or had noted antioxidant capacity. Lead candidates came from different drug classes that included angiotensin converting enzyme inhibitors or AT1 antagonists, COX2 inhibitors, as well as drugs mediated by histamine receptors. Surprisingly, different classes of anti-diabetic medications were observed to be useful including sulfonylureas and metformin. Using a hierarchical decision structure, we have identified several lead candidates. That no one drug or even drug class was completely successful across all parameters tested suggests the complexity of managing the consequences of galactic cosmic radiation exposure.