Panaxydol induces apoptosis through an increased intracellular calcium level,activation of JNK and p38 MAPK and NADPH oxidase-dependent generation of reactive oxygen species |
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Authors: | Joo Young Kim Su-Jin Yu Hyun Ju Oh Ji Young Lee Yongjin Kim Jeongwon Sohn |
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Institution: | (1) Department of Biochemistry, Korea University College of Medicine and Korean Institute of Molecular Medicine and Nutrition, 126-1 Anam-Dong 5 Ga, Sungbuk-Gu, Seoul, 136-705, Korea; |
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Abstract: | Panaxydol, a polyacetylenic compound derived from Panax ginseng roots, has been shown to inhibit the growth of cancer cells. In this study, we demonstrated that panaxydol induced apoptosis
preferentially in transformed cells with a minimal effect on non-transformed cells. Furthermore, panaxydol was shown to induce
apoptosis through an increase in intracellular Ca2+ concentration (Ca2+]i), activation of JNK and p38 MAPK, and generation of reactive oxygen species (ROS) initially by NADPH oxidase and then by
mitochondria. Panaxydol-induced apoptosis was caspase-dependent and occurred through a mitochondrial pathway. ROS generation
by NADPH oxidase was critical for panaxydol-induced apoptosis. Mitochondrial ROS production was also required, however, it
appeared to be secondary to the ROS generation by NADPH oxidase. Activation of NADPH oxidase was demonstrated by the membrane
translocation of regulatory p47phox and p67phox subunits and shown to be necessary for ROS generation by panaxydol treatment. Panaxydol triggered a rapid and sustained increase
of Ca2+]i, which resulted in activation of JNK and p38 MAPK. JNK and p38 MAPK play a key role in activation of NADPH oxidase, since
inhibition of their expression or activity abrogated membrane translocation of p47phox and p67phox subunits and ROS generation. In summary, these data indicate that panaxydol induces apoptosis preferentially in cancer cells,
and the signaling mechanisms involve a Ca2+]i increase, JNK and p38 MAPK activation, and ROS generation through NADPH oxidase and mitochondria. |
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