title: Synthetic protection short interfering RNA screen reveals glyburide as a novel radioprotector.
abstract: To assist in screening existing drugs for use as potential radioprotectors, we used a human unbiased 16,560 short interfering RNA (siRNA) library targeting the druggable genome. We performed a synthetic protection screen that was designed to identify genes that, when silenced, protected human glioblastoma T98G cells from gamma-radiation-induced cell death. We identified 116 candidate protective genes, then identified 10 small molecule inhibitors of 13 of these candidate gene products and tested their radioprotective effects. Glyburide, a clinically used second-generation hypoglycemic drug, effectively decreased radiation-induced cell death in several cell lines including T98G, glioblastoma U-87 MG, and normal lung epithelial BEAS-2B and in primary cultures of astrocytes. Glyburide significantly increased the survival of 32D cl3 murine hematopoietic progenitor cells when administrated before irradiation. Glyburide was radioprotective in vivo (90% of C57BL/6NHsd female mice 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 siRNA synthetic protection screening with a druggable genome library to identify new radioprotectors.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Jiang
authors.forename: Peter R
authors.initials: PR
authors.lastname: McDonald
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Dixon
authors.forename: Darcy
authors.initials: D
authors.lastname: Franicola
authors.forename: Xichen
authors.initials: X
authors.lastname: Zhang
authors.forename: Suhua
authors.initials: S
authors.lastname: Nie
authors.forename: Laura D
authors.initials: LD
authors.lastname: Epperly
authors.forename: Zhentai
authors.initials: Z
authors.lastname: Huang
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: John S
authors.initials: JS
authors.lastname: Lazo
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003114:Colony-Forming Units Assay; D004353:Drug Evaluation, Preclinical; D005260:Female; D015698:Genomic Library; D005905:Glyburide / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D051379:Mice; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D014916:Whole-Body Irradiation
chemical_list: D007004:Hypoglycemic Agents; D034741:RNA, Small Interfering; D011837:Radiation-Protective Agents; D005905:Glyburide