Small-Molecule Suppressors of Cytokine-Induced beta-Cell Apoptosis.
Pancreatic beta-cell apoptosis is a critical event during the development of type-1 diabetes. The identification of small molecules capable of preventing cytokine-induced apoptosis could lead to avenues for therapeutic intervention. We developed a set of phenotypic cell-based assays designed to identify such small-molecule suppressors. Rat INS-1E cells were simultaneously treated with a cocktail of inflammatory cytokines and a collection of 2,240 diverse small molecules and screened using an assay for cellular ATP levels. Forty-nine top-scoring compounds included glucocorticoids, several pyrazole derivatives, and known inhibitors of glycogen synthase kinase-3beta. Two compounds were able to increase cellular ATP levels, reduce caspase-3 activity and nitrite production, and increase glucose-stimulated insulin secretion in the presence of cytokines. These results indicate that small molecules identified by this screening approach may protect beta cells from autoimmune attack and may be good candidates for therapeutic intervention in early stages of type-1 diabetes.
Chou
Danny Hung-Chieh
DH
Bodycombe
Nicole E
NE
Carrinski
Hyman A
HA
Lewis
Timothy A
TA
Clemons
Paul A
PA
Schreiber
Stuart L
SL
Wagner
Bridget K
BK
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D057166:High-Throughput Screening Assays; D007004:Hypoglycemic Agents / Q000302:isolation & purification* / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D054852:Small Molecule Libraries
D016207:Cytokines; D007004:Hypoglycemic Agents; D054852:Small Molecule Libraries