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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)
장병철백원기서민호권택규박종욱김상표신동훈송대규배재훈문교철서성일
Alternative 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
Publication Year
2004
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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