The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) induces apoptosis in Mycosis fungoides/Sezary syndrome cells.
The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) induces apoptosis in Mycosis fungoides/Sezary syndrome cells.
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新型合成齐墩果烷三萜 CDDO（2-cyano-3, 12-dioxolean-1, 9-dien-28-oic 酸）可诱导蕈样肉芽肿/Sezary 综合征细胞凋亡。
DOI：
10.1111/j.0022-202x.2004.23207.x
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Duvic,Madeleine
中科院分区：
文献类型：
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作者：
Zhang,Chunlei;Ni,Xiao;Konopleva,Marina;Andreeff,Michael;Duvic,Madeleine
合成的齐墩果烷三萜类化合物CDDO(2-氰基-3，12-二氧杂环烯-1，9-二烯-28-酸)可作为过氧化物酶体增殖物激活受体-γ(PPAR-γ)的配体，具有抑制细胞增殖、诱导肿瘤细胞分化和凋亡的作用。贝沙罗汀是一种具有RXR选择性的维甲酸类化合物，可诱导真菌病(MF)和S综合征(SS)细胞的凋亡。由于PPAR-γ和RXR受体可以形成异二聚体，我们研究了CDDO及其与贝沙罗汀的协同作用对MF/SS细胞系(MJ、HUT78和HH)以及SS患者新鲜分离的具有非典型T细胞(CD_4+CD_(26-))的外周血淋巴细胞凋亡的影响。与赋形剂对照组相比，1-5μM染毒48h可诱导3株MF/SS细胞和患者外周血淋巴细胞呈浓度依赖性的凋亡。贝沙罗汀增强了CDDO诱导的这些细胞的凋亡。PPAR-γ在MJ、Hut78和HH细胞中均有表达，但分别下降了47%、42%和77%。CDDO处理后，MJ、Hut78和HH细胞中抗凋亡蛋白bclxl下降了69%，Hut78下降了31%，HH细胞下降了59%，caspase-3被激活。有趣的是，PPAR-γ拮抗剂T007不能阻断CDO诱导的细胞凋亡，而更有效的PPAR-γ激动剂罗格列酮需要比CDO高得多的浓度(>；50μM)才能诱导MF/SS细胞凋亡。综上所述，镉可诱导MF/SS细胞的凋亡，这种作用可被贝沙罗汀进一步增强，并降低PPAR-γ和bclxl蛋白的表达。CDO对MF/SS细胞的作用可能至少部分是通过PPAR-γ非依赖性机制实现的。我们的发现为进一步研究CDDO单独或与贝沙罗汀联合治疗MF/SS患者的临床潜力提供了理论基础。
The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) can serve as a ligand for the peroxisome proliferator activator receptor-γ (PPAR-γ) and has been shown to inhibit cell proliferation, and to induce differentiation and apoptosis in tumor cell lines. Bexarotene is an RXR-selective retinoid that can induce apoptosis of mycosis fungoides (MF) and Sézary syndrome (SS) cells. Since the PPAR-γ and RXR receptors can form heterodimers, we studied the effects of CDDO and its synergism with bexarotene on apoptosis in MF/SS cell lines (MJ, Hut78, and HH) and freshly isolated peripheral blood lymphocytes (PBL) from SS patients with circulating atypical T cells (CD4+CD26-). CDDO treatment at 1–5 μM for 48 h caused a concentration-dependent apoptosis in three MF/SS cell lines and patients' PBL compared to vehicle controls. Bexarotene augmented CDDO-induced apoptosis in these cells. PPAR-γ was expressed but decreased by 47% in MJ, 42% in Hut78, and 77% in HH cells following CDDO treatment. The anti-apoptotic protein bcl-xL, but not bcl-2, was decreased by 69% in MJ, 31% in Hut78, and 59% in HH cells and caspase-3 was activated following CDDO treatment. Interestingly, the PPAR-γ antagonist T007 did not block CDDO-induced apoptosis, and the more potent PPAR-γ agonist rosiglitazone required much higher concentrations (>50 μM) than CDDO to induce apoptosis in MF/SS cells. In summary, CDDO induces apoptosis that is further enhanced by bexarotene and decreases the PPAR-γ and bcl-xL proteins in MF/SS cells. CDDO's effects on MF/SS cells may be at least partly mediated through a PPAR-γ-independent mechanism. Our findings suggest the rationale for further investigation of the clinical potential of CDDO, either alone or in combination with bexarotene for MF/SS patients.