Cyclosporine A and bromocriptine attenuate cell death mediated by intracellular calcium mobilization

Abstract

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 3,280 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. [BMB Reports 2012; 45(8): 482-487]

The gp130/STAT3-endoplasmic reticulum stress axis regulates hepatocyte necroptosis in acute liver injury

“…The cells were cultured in RPMI-1640 supplemented with 10% fetal bovine serum, 100 units/mL of penicillin, and 100 μg/mL of streptomycin. To induce ER stress, LO2 cells were treated with TG (0.5 μmol/L, Sigma, St. Louis, MO, USA) for 24 or 48 h. TG is a ER stress inducer that disrupts intracellular calcium homeostasis in the ER membrane and inhibits its ability to fold and process proteins ( 25 ). One control group was untreated and the other was treated with vehicle dimethyl sulfoxide (DMSO).…”