Cyclosporine A and bromocriptine attenuate cell death mediated by intracellular calcium mobilization.
To identify the novel inhibitors of endoplasmic reticulum stress-induced cell death, we performed a high throughput assay with a chemical library containing a total of 3280 bioactive small molecules. Cyclosporine A and bromocriptine were identified as potent inhibitors of thapsigargiin-induced cell death (cut-off at 4σ standard score) . However, U74389G, the potent inhibitor of lipid peroxidation had lower activity in inhibiting cell death. The inhibition effect of cyclosporine A and bromocriptine was specific for only thapsigargin-induced cell death. The mechanism of inhibition by these compounds was identified as modification of the expression of glucose regulated protein-78 (GRP-78/Bip) and inhibition of phosphorylation of p38 mitogen activated protein kinase (MAPK). However, these compounds did not inhibit the same events triggered by tunicamycin, which was in agreement with the cell survival data. We suggest that the induction of protective unfolded protein response by these compounds confers resistance to cell death. In summary, we identified compounds that may provide insights on cell death mechanisms stimulated by ER stress.
Asan Institute for Life Science, Asan Medical Center, Seoul, Korea. ik.kim@amc.seoul.kr
In Ki
IK
Kim
So Jung
SJ
Park
Jhang Ho
JH
Park
Seung-Ho
SH
Lee
Sung Eun
SE
Hong
John C
JC
Reed
D017209:Apoptosis / Q000187:drug effects*; D001971:Bromocriptine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D045325:HCT116 Cells; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019284:Thapsigargin / Q000633:toxicity; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D014415:Tunicamycin; D001971:Bromocriptine; D019284:Thapsigargin; D016572:Cyclosporine; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium