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DESIPRAMINE‐INDUCED Ca 2+ ‐INDEPENDENT APOPTOSIS IN MG63 HUMAN OSTEOSARCOMA CELLS: DEPENDENCE ON P38 MITOGEN‐ACTIVATED PROTEIN KINASE‐REGULATED ACTIVATION OF CASPASE 3
Author(s) -
Lu Ti,
Huang ChorngChih,
Lu YihChau,
Lin KoLong,
Liu ShiuhIn,
Wang BeingWhey,
Chang PoMin,
Chen IShu,
Chen ShengShih,
Tsai JengYu,
Chou ChiangTing,
Jan ChungRen
Publication year - 2009
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2008.05065.x
Subject(s) - desipramine , mapk/erk pathway , p38 mitogen activated protein kinases , protein kinase a , apoptosis , programmed cell death , kinase , microbiology and biotechnology , mitogen activated protein kinase , bapta , caspase 3 , chemistry , biology , cancer research , extracellular , endocrinology , biochemistry , antidepressant , hippocampus
SUMMARY1 It has been shown that the antidepressant desipramine is able to induce increases in [Ca 2+ ] i and cell death in MG63 human osteosacroma cells, but whether apoptosis is involved is unclear. In the present study, the effect of desipramine on apoptosis and the underlying mechanisms were explored. It was demonstrated that desipramine induced cell death in a concentration‐ and time‐dependent manner. 2 Cells treated with 100–800 mmol/L desipramine showed typical apoptotic features, including an increase in sub‐diploid nuclei and activation of caspase 3, indicating that these cells underwent apoptosis. Immunoblotting revealed that 100 mmol/L desipramine activated extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK) and p38 mitogen‐activated protein kinase (MAPK). Although pretreatment of cells with 20 mmol/L PD98059 (an ERK inhibitor) or 20 mmol/L SP600125 (an inhibitor of JNK) did not inhibit cell death, the addition of 20 mmol/L SB203580 (a p38 MAPK inhibitor) partially rescued cells from apoptosis. Desipramine‐induced caspase 3 activation required p38 MAPK activation. 3 Pretreatment of cells with BAPTA/AM (20 mmol/L) to prevent desipramine‐induced increases in [Ca 2+ ] i did not protect cells from death. 4 The results of the present study suggest that, in MG63 human osteosarcoma cells, desipramine causes Ca 2+ ‐independent apoptosis by inducing p38 MAPK‐associated activation of caspase 3.