Inhibiting glycogen synthase kinase-3 mitigates the hematopoietic acute radiation syndrome in mice.
Exposure to a nuclear accident or radiological attack can cause death from acute radiation syndrome (ARS), which results from radiation injury to vital organs such as the hematopoietic system. However, the U.S. Food and Drug Administration (FDA) has not approved any medical countermeasures for this specific purpose. With growing concern over nuclear terrorism, there is an urgent need to develop small molecule deliverables that mitigate mortality from ARS. One emerging modulator of hematopoietic stem/progenitor cell (HSPC) activity is glycogen synthase kinase-3 (GSK-3). The inhibition of GSK-3 has been shown to augment hematopoietic repopulation in mouse models of bone marrow transplantation. In this study, we performed an in vitro screen using irradiated bone marrow mononuclear cells (BM-MNCs) to test the effects of four GSK-3 inhibitors: CHIR99021; 6-Bromoindirubin-3'-oxime (BIO); SB415286; and SB216763. This screen showed that SB216763 significantly increased the frequency of c-Kit(+) Lin(-) Sca1(+) (KLS) cells and hematopoietic colony-forming cells in irradiated BM-MNCs. Importantly, administration of a single dose of SB216763 to C57BL/6J mice by subcutaneous injection 24 h after total-body irradiation significantly improved hematopoietic recovery and mitigated hematopoietic ARS. Collectively, our results demonstrate that the GSK-3 inhibitor SB216763 is an effective medical countermeasure against acute radiation injury of the hematopoietic system.
a  Department of Radiation Oncology;
Chang-Lung
CL
Lee
William E
WE
Lento
Katherine D
KD
Castle
Nelson J
NJ
Chao
David G
DG
Kirsch
D054508:Acute Radiation Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000627:Aminophenols / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001853:Bone Marrow / Q000473:pathology; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004353:Drug Evaluation, Preclinical; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000528:radiation effects; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014916:Whole-Body Irradiation / Q000009:adverse effects
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; C483321:6-bromoindirubin-3'-oxime; D000627:Aminophenols; C473711:Chir 99021; D007211:Indoles; D008301:Maleimides; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C417521:SB 216763; D038362:Glycogen Synthase Kinase 3