Synthetic Protection Short Interfering RNA Screen Reveals Glyburide as aNovel Radioprotector

摘要

To assist in screening existing drugs for use as potentialradioprotectors, we used a human unbiased 16,560 shortinterfering RNA (siRNA) library targeting the druggablegenome. We performed a synthetic protection screen that wasdesigned to identify genes that, when silenced, protected humanglioblastoma T98G cells from y-radiation-induced cell death.We identified 116 candidate protective genes, then identified 10small molecule inhibitors of 13 of these candidate gene productsand tested their radioprotective effects. Glyburide, a clinicallyused second-generation hypoglycemic drug, effectively decreasedradiation-induced cell death in several cell lines including T98G,glioblastoma U-87 MG, and normal lung epithelial BEAS-2Band in primary cultures of astrocytes. Glyburide significantlyincreased the survival of 32D cl3 murine hematopoieticprogenitor cells when administrated before irradiation. Glybur-ide was radioprotective in vivo (90% of C57BL/6NHsd femalemice pretreated with 10 mg/kg glyburide survived 9.5 Gy total-body irradiation compared to 42% of irradiated controls, P =0.0249). These results demonstrate the power of unbiased siRNAsynthetic protection screening with a druggable genome library to identify new radioprotectors.