Desipramine-induced apoptosis in human PC3 prostate cancer cells:: Activation of JNK kinase and caspase-3 pathways and a protective role of [Ca2+]i elevation

The antidepressant desipramine has been shown to induce a rise in cytosolic Ca(2+) levels ([Ca(2+)](i)) and cytotoxicity in human PC3 prostate cancer cells, but the mechanisms underlying its cytotoxic effect is unclear. Cell viability was examined by WST-1 assays. Apoptosis was assessed by propidium iodide staining and an increase in caspase-3 activation. Phosphorylation of protein kinases was analyzed by immunoblotting. Desipramine caused cell death via apoptosis in a concentration-dependent manner. Immunoblotting data revealed that desipramine activated the phosphorylation of c-Jun NH2-terminal kinase (JNK), but not extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). SP600125 (a selective JNK inhibitor) partially prevented cells from apoptosis. Pretreatment with BAPTA/AM, aCa(2+) chelator, to prevent desipramine-induced [Ca(2+)](i) rises worsened desipramine-induced cytotoxicity. Immunoblotting data suggest that BAPTA/AM pretreatment enhanced desipramine-evoked JNK phosphorylation and caspase-3 cleavage. The results suggest that in PC3 cells, desipramine caused apoptosis via inducing JNK-associated caspase-3 activation, and [Ca(2+)](i) rises may slow down or alleviate desipramine-induced cytotoxicity. (C) 2008 Elsevier Ireland Ltd. All rights reserved.