The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance.
The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance.
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发表时间：
2003-09
期刊：
影响因子：
11.2
通讯作者：
T. Ikeda;M. Sporn;T. Honda;G. Gribble;D. Kufe
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文献类型：
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作者：
T. Ikeda;M. Sporn;T. Honda;G. Gribble;D. Kufe
新型齐墩果烷三萜类化合物2-氰基-3，12-二氧杂环烯-1，9-二烯-28-酸(CDDO)通过激活外源性caspase-8途径诱导人白血病细胞凋亡。CDDO促细胞凋亡作用的机制尚不清楚。本研究表明，CDDO能激活U-937白血病细胞的c-jun氨基末端激酶和p38丝裂原活化蛋白激酶。结果还表明，CDDO通过增加细胞内活性氧水平和降低细胞内谷胱甘肽(GSH)浓度来激活应激激酶。C-28甲酯(CDDO-Me)和C-28咪唑烷酸酯(CDDO-Im)的衍生物也得到了类似的结果。结果还表明，CDO诱导的：(A)Jun NH(2)-末端激酶的兴奋；(B)caspase-8的激活；(C)线粒体跨膜电位的丧失；(D)细胞色素c的释放；(E)caspase-3的裂解可被抗氧化剂N-乙酰-L半胱氨酸和谷胱甘肽阻断，但不能被半胱氨酸阻断。与此结果相一致的是，N-乙酰-L-半胱氨酸和谷胱甘肽也可阻断镉诱导的细胞凋亡。这些发现表明，CDDO及其衍生物破坏细胞内氧化还原平衡，从而诱导细胞凋亡。
The novel oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) induces apoptosis of human leukemia cells by activation of the extrinsic caspase-8 pathway. The mechanisms responsible for the proapoptotic effects of CDDO are unknown. The present studies demonstrate that CDDO activates the c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase in U-937 leukemia cells. The results also show that CDDO activates stress kinases by increasing levels of reactive oxygen species and decreasing intracellular glutathione (GSH) concentrations. Similar findings were obtained with the C-28 methyl ester (CDDO-Me) and C-28 imidazolide ester (CDDO-Im) derivatives. The results also demonstrate that CDDO-induced: (a) stimulation of Jun NH(2)-terminal kinase; (b) activation of caspase-8; (c) loss of mitochondrial transmembrane potential; (d) release of cytochrome c; and (e) cleavage of caspase-3 are blocked by pretreatment with the antioxidant N-acetyl-L-cysteine and GSH but not with cysteine. In concert with these results, CDDO-induced apoptosis is also abrogated by N-acetyl-L-cysteine and GSH. These findings demonstrate that CDDO and its derivatives disrupt intracellular redox balance and thereby induce apoptosis.