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

To identify the novel inhibitors of endoplasmic reticulumstress-induced cell death, we performed a high throughput assaywith a chemical library containing a total of 3280 bioactive smallmolecules. Cyclosporine A and bromocriptine were identified aspotent inhibitors of thapsigargiin-induced cell death (cut-off at4σ standard score) . However, U74389G, the potent inhibitor oflipid peroxidation had lower activity in inhibiting cell death. Theinhibition effect of cyclosporine A and bromocriptine wasspecific for only thapsigargin-induced cell death. The mechanismof inhibition by these compounds was identified as modificationof the expression of glucose regulated protein-78 (GRP-78/Bip)and inhibition of phosphorylation of p38 mitogen activatedprotein kinase (MAPK). However, these compounds did notinhibit the same events triggered by tunicamycin, which was inagreement with the cell survival data. We suggest that theinduction of protective unfolded protein response by thesecompounds confers resistance to cell death. In summary, weidentified compounds that may provide insights on cell deathmechanisms stimulated by ER stress.