Synthetic protection short interfering RNA screen reveals glyburide as a novel radioprotector.

Full 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.

Author information

Author/s: Jiang, Jianfei (J); McDonald, Peter R (PR); Dixon, Tracy M (TM); Franicola, Darcy (D); Zhang, Xichen (X); Nie, Suhua (S); Epperly, Laura D (LD); Huang, Zhentai (Z); Kagan, Valerian E (VE); Lazo, John S (JS); Epperly, Michael W (MW); Greenberger, Joel S (JS);

Affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.

Grants: CA78039 (Agency:NCI NIH HHS) ; U19 AI 068021 (Agency:NIAID NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Radiation research (Radiat Res), published in United States. (Language: eng)

Reference: 2009-Oct; vol 172 (issue 4) : pp 414-22

Dates: Created 2009/09/23; Completed 2009/11/05;

PMID: 19772462, status: MEDLINE (last retrieval date: 11/5/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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