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KMID : 0617220020130010165
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Duksung Bulletin Phamaceutical Sciences
2002 Volume.13 No. 1 p.165 ~ p.169
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Role of Calmodulin in the Generation of Reactive Oxygen Species and Apoptosis Induced by Tamoxifen in HepG2 Human Hepatoma Cells
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Lee Yong-Soo
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Abstract
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Tamoxifen, an antiestrogen, has previously been shown to induce apoptosis in HepG2 human hepatoblastoma cells through activation of the pathways independent of estrogen receptors, i.e., intracellular Ca^2+ increase and generation of reactive oxygen species (ROS). However, the mechanism of tamoxifen to link increased intracellular Ca^2+ to ROS generation is currently unknown. Thus, in this study we investigated the possible involvement of calmodulin, a Ca^2+ activated protein, and Ca^2+/ calmodulin-dependent protein kinase Ⅱ in the above tamoxifen-induced events. Treatment with calmodulin antagonists (calmidazolium and trifluoroperazine) or specific inhibitors of Ca^2+/calmodulin-dependent protein kinase Ⅱ (KN-93 and KN-62) inhibited the tamoxifen-induced apoptosis in a dose-dependent manner. In addition, these agents blocked the tamoxifen-induced ROS generation in a concentration-dependent fashion, which was completely suppressed by intracellular Ca^2+ chelation. These results demonstrate for the first time that, despite of its well-known direct calmodulin-inhibitory activity, tamoxifen may generate ROS and induce apoptosis through indirect activation of calmodulin and Ca^2+/calmodulin-dependent protein kinase Ⅱ in HepG2 cells.
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KEYWORD
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