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Tetrandrine-induced apoptosis is mediated by activation of caspases and PKC-δ in U937 cells

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Author(s)
Byeong-Churl JangKi-Jo LimJi-Hye PaikJae-We ChoWon-Ki BaekMin-Ho SuhJae-Bok ParkTaek Kyu KwonJong-Wook ParkSang-Pyo KimDong-Hoon ShinDae-kyu SongJae-Hoon BaeKyo-Cheol MunSeong-Il Suh
Keimyung Author(s)
Jang, Byeong ChurlBaek, Won KiSuh, Min HoKwon, Taeg KyuPark, Jong WookKim, Sang PyoShin, Dong HoonSong, Dae KyuBae, Jae HoonMun, Kyo CheolSuh, Seong Il
Department
Dept. of Molecular Medicine (분자의학)
Dept. of Microbiology (미생물학)
Dept. of Immunology (면역학)
Dept. of Pathology (병리학)
Dept. of Preventive Medicine (예방의학)
Dept. of Biochemistry (생화학)
Dept. of Physiology (생리학)
Institute for Medical Science (의과학연구소)
Journal Title
Biochemical Pharmacology
Issued Date
2004
Volume
67
Issue
10
Abstract
Tetrandrine, which is isolated from Chinese herb Stephania tetrandrae, possesses anti-inflammatory, immunosuppressive, and cytoprotective properties. Though it was previously shown that tetrandrine causes a G1 blockade and apoptosis in various cell types, however, the mechanism by which tetrandrine initiates apoptosis remains poorly understood. In present study, we investigated the mechanisms of apoptosis induced by tetrandrine in U937 leukemia cells. Tetrandrine inhibited U937 cell growth by inducing apoptosis. After treatment of U937 cells with tetrandrine (10 μM) for 24 h, alteration of cell morphology, chromatin fragmentation, cytochrome c release, and caspase activation were observed. Tetrandrine also induced early oxidative stress, which resulted in activation of JNK, but not ERK and p38 MAPK. A broad-spectrum caspase inhibitor and antioxidants significantly blocked tetrandrine-induced caspase-3 activation. However, inhibition of the JNK activity with SP600125 did not block tetrandrine-induced apoptosis. Tetrandrine-induced apoptosis of U937 cells also required activity of PKC-δ, because pretreatment with a specific PKC-δ inhibitor greatly blocked tetrandrine-induced caspase-3 activation. In addition, the apoptotic response to tetrandrine was significantly attenuated in dominant-negative PKC-δ transfected MCF-7 cells, suggesting that PKC-δ plays an important role in tetrandrine-induced apoptosis and can induce caspase activation. These results suggest that tetrandrine induces oxidative stress, JNK activation, and caspase activation. However, JNK activation by ROS is not involved in the tetrandrine-induced apoptosis. In addition, tetrandrine induces caspase-dependent generation of a catalytically active fragment of PKC-δ, and this fragment also appears to play a role in the activation of caspases. Keywords
Tetrandrine;
Apoptosis;
Caspase;
ROS;
JNK;
PKC-δ
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