The novel triterpenoid 2-cyano-3,12-dioxooleana-1, 9-dien-28-oic acid (CDDO) induces apoptosis of human diffuse large B-cell lymphoma cells through a peroxisome proliferator-activated receptor γ-independent pathway
The novel triterpenoid 2-cyano-3,12-dioxooleana-1, 9-dien-28-oic acid (CDDO) induces apoptosis of human diffuse large B-cell lymphoma cells through a peroxisome proliferator-activated receptor γ-independent pathway
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DOI：
10.1016/j.exphem.2006.04.026
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发表时间：
2006-09-01
影响因子：
2.6
通讯作者：
Bernstein, Steven H.
中科院分区：
文献类型：
--
作者：
Ray, Denise M.;Morse, Kimberly M.;Bernstein, Steven H.
目标。转录因子过氧化物酶体增殖物激活受体γ(PPARγ)的配体是一类新型的抗肿瘤药物。在此，我们研究了PPARγ配体三萜类CDDO作为抗癌药物对人弥漫性大B细胞淋巴瘤(DLBCL)细胞的潜在作用。采用四甲基偶氮唑蓝((3-(4，5-dimethylthiazole2-yl)-2，5-diphenyltetrazolium)比色法、H-3-胸腺嘧啶核苷掺入法和Annexin-V/碘化丙啶染色方法检测镉对生发中心和活化B细胞亚型的诱导作用。采用PPAR-γ小分子拮抗剂、转染实验、DNA结合实验、免疫荧光、Western blotting和核因子-kappa B抑制剂等方法，检测PPAR-γ和核因子-kappaB对CDD细胞毒作用的影响。人DLBCL细胞表达PPAR-γ，CDDO激活PPAR-γ。在这两种亚型的DLBCL细胞中，CDDO抑制增殖，具有细胞毒作用，并诱导细胞凋亡。CDDO杀伤DLBCL细胞的能力不依赖于PPAR-γ的激活。有趣的是，CDDO暴露导致了核因子-kappaB的p50和p65亚基的激活，并且CDDO与核因子-kappaB抑制剂联合使用导致DLBCL细胞死亡增加，表明核因子-kappaB的激活是一种生存信号。这些发现支持CDDO单独或联合使用核因子-kappaB抑制剂作为治疗DLBCL患者的一种新疗法的潜力。(C)2006年国际实验血液学学会。由爱思唯尔公司出版。
Objective. Ligands for the transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma) are emerging as a new class of antitumor agents. Herein, we investigated the triterpenoid CDDO, a PPAR gamma ligand, for its potential as an anticancer agent on human diffuse large B-cell lymphoma (DLBCL) cells.Methods. The ability of CDDO to induce apoptosis in human DLBCL cells of both the germinal center and activated B-cell subtypes was determined by MTT (3-(4,5-dimethylthiazole2-yl)-2,5-diphenyltetrazolium bromide) assay, H-3-thymidine incorporation, and Annexin-V/ propidium iodide staining. Small molecule antagonists of PPAR gamma, transfection assays, DNA binding assays, immunofluorescence, Western blotting, and NF-kappa B inhibitors were utilized to determine the contribution of PPAR gamma and NF-kappa B to the cytotoxic effects of CDDO.Results. Human DLBCL cells express PPAR gamma and PPAR gamma is activated by CDDO. In both subtypes of DLBCL cells CDDO inhibited proliferation, was cytotoxic, and induced apoptosis. The ability of CDDO to kill DLBCL cells was found to be independent of PPAR gamma activation. Interestingly, CDDO exposure resulted in activation of the p50 and p65 subunits of NF-kappa B. Moreover, the combination of CDDO with NF-kappa B inhibitors resulted in enhanced DLBCL cell death, indicating that NF-kappa B activation was a prosurvival signal.Conclusion. These findings support the potential of CDDO, alone or in combination with NF-kappa B inhibitors, as a novel therapy for patients with DLBCL. (c) 2006 International Society for Experimental Hematology. Published by Elsevier Inc.