Paroxetine-induced apoptosis in human osteosarcoma cells: activation of p38 MAP kinase and caspase-3 pathways without involvement of [Ca2+]i elevation.
Selective serotonin reuptake inhibitors (SSRIs), a group of antidepressants, are generally used for treatment of various mood and anxiety disorders. There has been much research showing the anti-tumor and cytotoxic activities of some antidepressants; but the detailed mechanisms were unclear. In cultured human osteosarcoma cells (MG63), paroxetine reduced cell viability in a concentration- and time-dependent manner. Paroxetine caused apoptosis as assessed by propidium iodide-stained cells and increased caspase-3 activation. Although immunoblotting data revealed that paroxetine could activate the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), only SB203580 (a p38 MAPK inhibitor) partially prevented cells from apoptosis. Paroxetine also induced [Ca(2+)](i) increases which involved the mobilization of intracellular Ca(2+) stored in the endoplasmic reticulum and Ca(2+) influx from extracellular medium. However, pretreatment with BAPTA/AM, a Ca(2+) chelator, to prevent paroxetine-induced [Ca(2+)](i) increases did not protect cells from death. The results suggest that in MG63 cells, paroxetine caused Ca(2+)-independent apoptosis via inducing p38 MAPK-associated caspase-3 activation.
Chou
Chiang-Ting
CT
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, 813, Taiwan.
He
Shiping
S
Jan
Chung-Ren
CR
D017209:Apoptosis / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D012516:Osteosarcoma; D017374:Paroxetine / Q000633:toxicity*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D053148:Caspase 3; D002614:Chelating Agents; D004533:Egtazic Acid; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D007093:Imidazoles; D048031:JNK Mitogen-Activated Protein Kinases; D017374:Paroxetine; D011725:Pyridines; D017367:Selective Serotonin Reuptake Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C093642:SB 203580