A New Class of Molecular Targeted Radioprotectors: GSK-3beta Inhibitors

Journal Article · Mon Feb 01 04:00:00 EST 2010 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2009.09.024· OSTI ID:21372074

Thotala, Dinesh K; Ling, Geng ^[1]; Dickey, Amy K ^[2]; Yazlovitskaya, Eugenia M ^[1]

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1. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States)
2. Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN (United States)

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.

• OSTI ID: 21372074
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 2 Vol. 76; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
APOPTOSIS
BODY
CARBOHYDRATES
DIGESTIVE SYSTEM
DRUGS
GASTROINTESTINAL TRACT
GLYCOGEN
INTESTINES
MAMMALS
MEDICINE
MICE
NUCLEAR MEDICINE
ORGANIC COMPOUNDS
ORGANS
POLYSACCHARIDES
RADIATION PROTECTION
RADIOLOGY
RADIOPROTECTIVE SUBSTANCES
RADIOTHERAPY
RESPONSE MODIFYING FACTORS
RODENTS
SACCHARIDES
SMALL INTESTINE
STANDARD OF LIVING
THERAPY
VERTEBRATES