Identification of Compounds Protecting Pancreatic Islets against Oxidative Stress using a 3D Pseudoislet Screening Platform

Oxidative stress leads to a lower success rate of clinical islet transplantation. Here, FDA‐approved compounds are screened for their potential to decrease oxidative stress and to protect or enhance pancreatic islet viability and function. Studies are performed on in vitro “pseudoislet” spheroids, which are pre‐incubated with 1280 different compounds and subjected to oxidative stress. Cell viability and oxidative stress levels are determined using a high‐throughput fluorescence microscopy pipeline. Initial screening on cell viability results in 59 candidates. The top ten candidates are subsequently screened for their potential to decrease induced oxidative stress, and eight compounds efficient reduction of induced oxidative stress in both alpha and beta cells by 25–50%. After further characterization, the compound sulfisoxazole is found to be the most capable of reducing oxidative stress, also at short pre‐incubation times, which is validated in primary human islets, where low oxidative stress levels and islet function are maintained. This study shows an effective screening strategy with 3D cell aggregates based on cell viability and oxidative stress, which leads to the discovery of several compounds with antioxidant capacity. The top candidate, sulfisoxazole is effective after a 30 min pre‐incubation, maintains baseline islet function, and may help alleviate oxidative stress in pancreatic islets. To improve pancreatic islet function by reducing oxidative stress, 1280 FDA‐approved compounds are screened of which 59 compounds can maintain pseudoislet viability upon induced oxidative stress. Of these 59 compounds, ten compounds mitigate induced oxidative stress. The top candidate, sulfisoxazole lowers oxidative stress in the pseudoislet model and also preserves primary human islet function in vitro.