A new class of molecular targeted radioprotectors: GSK-3beta inhibitors.

Thotala DK, Geng L, Dickey AK, Hallahan DE, Yazlovitskaya EM
Int J Radiat Oncol Biol Phys. 2010 76 (2): 557-65

PMID: 20117291 · PMCID: PMC2873869 · DOI:10.1016/j.ijrobp.2009.09.024

PURPOSE - Development of new treatments is critical to effective protection against radiation-induced injury. We investigate the potential of developing small-molecule inhibitors of glycogen synthase kinase 3beta (GSK-3beta)-SB216763 or SB415286-as radioprotective agents to attenuate intestinal injury.

METHODS AND MATERIALS - A survival study was done by use of C57BL/6J mice to evaluate the radioprotective effect of GSK-3beta inhibitors. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and immunohistochemical staining for Bax and Bcl-2 were used to assess apoptosis in the small intestines of the treated mice. A clonogenic survival study, apoptosis assays (staining with annexin V or 4',6-diamidino-2-phenylindole), and immunoblot analysis of beta-catenin, Bcl-2, Bax, and caspase 3 were done by use of Rat intestinal epithelial cell line IEC-6 cells.

RESULTS - Pretreatment with SB415286 significantly improved survival of mice irradiated with 8 and 12 Gy. Mice pretreated with SB216763 or SB415286 showed a significant reduction in TUNEL- and Bax-positive cells and an increase in Bcl-2-positive cells in intestinal crypts at 4 and/or 12 h after radiation with 4 and/or 8 Gy compared with radiation alone. Pretreatment of irradiated IEC-6 cells with GSK-3beta inhibitors significantly increased clonogenic survival compared with cells treated with radiation alone. This increase was due to the attenuation of radiation-induced apoptosis, as shown by annexin V and 4',6-diamidino-2-phenylindole assays, as well as immunoblot analysis of Bcl-2, Bax, and caspase 3.

CONCLUSIONS - Glycogen synthase kinase 3beta small-molecule inhibitors protect mouse intestine from radiation-induced damage in cell culture and in vivo and improve survival of mice. Molecular mechanisms of this protection involve attenuated radiation-induced apoptosis regulated by Bcl-2, Bax, and caspase 3. Therefore GSK-3beta inhibitors reduce deleterious consequences of intestinal irradiation and thereby improve quality of life during radiation therapy.

Copyright 2010 Elsevier Inc. All rights reserved.

MeSH Terms (19)

Aminophenols Animals Apoptosis bcl-2-Associated X Protein beta Catenin Caspase 3 Cell Line Cell Survival Glycogen Synthase Kinase 3 Glycogen Synthase Kinase 3 beta Indoles In Situ Nick-End Labeling Intestines Maleimides Mice Mice, Inbred C57BL Radiation-Protective Agents Radiation Injuries, Experimental Rats

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