Ikeda Takashi, Nakata Yukiko, Kimura Fumihiko, Sato Ken, Anderson Kenneth, Motoyoshi Kazuo, Sporn Michael, Kufe Donald
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Mol Cancer Ther. 2004 Jan;3(1):39-45.
The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-L-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.
合成齐墩果烷三萜类化合物2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸（CDDO）及其化学衍生物可诱导人白血病细胞分化和凋亡。然而，负责CDDO作用的精确机制仍不清楚。在本研究中，我们检测了CDDO及其C-28咪唑酯（CDDO-Im）对多发性骨髓瘤（MM）细胞凋亡的影响。结果表明，CDDO和CDDO-Im都是MM细胞凋亡的有效诱导剂，且CDDO-Im比CDDO更具活性。CDDO-Im处理与以下情况相关：（a）谷胱甘肽耗竭；（b）活性氧增加；（c）Fas相关死亡结构域（FADD）样白细胞介素-1转化酶（FLICE）抑制蛋白减少；（d）半胱天冬酶-8激活；（e）线粒体跨膜电位降低。还原剂N-乙酰-L-半胱氨酸、二硫苏糖醇和过氧化氢酶可抑制这些CDDO-Im诱导的促凋亡信号中的每一个。用z-IETD-fmk抑制半胱天冬酶-8也可消除CDDO-Im诱导的线粒体跨膜电位降低并抑制凋亡。这些结果表明，CDDO-Im破坏细胞内氧化还原平衡，从而激活外源性半胱天冬酶-8依赖性凋亡途径。我们进一步表明CDDO-Im在亚微摩尔浓度下可诱导原代MM细胞凋亡，且MM细胞比正常骨髓单个核细胞对该药物更敏感。这些结果表明CDDO化合物有潜力作为治疗MM的新型药物。
