Anti-Leukemic Activity of the Novel Triterpeniod CDDO

描述（由申请人提供）：急性骨髓性白血病的治疗结果 白血病（AML）已经二十多年没有改变，除了改善的 急性早幼粒细胞白血病患者的缓解率和生存率 用全反式维甲酸治疗2-氰基-3，12-二氧代-1，9-二烯-28-羧酸 酸（CDDO）是一种新的三萜类化合物，具有独特的性质： 分化，抑制细胞生长并诱导白血病细胞凋亡 细胞系和来自AML患者的原始样本中， 慢粒。CDDO连接并反式激活核转录因子 过氧化物酶体增殖物激活受体γ（PPARgamma）， 异二聚体与类维生素A X受体（RXR）。我们在此建议， CDDO活性在AML中的疗效和机制的初步研究， 开发CDDO作为治疗血液病的药物的目标 恶性肿瘤。首先，我们将进一步研究生长抑制作用 CDDO对悬浮液中的原代AML和正常造血祖细胞的作用， 克隆形成测定系统。其次，我们将定义CDDO对 PPARgamma的转录功能，我们发现它在细胞中高度表达。 急性髓细胞白血病第三，我们将阐明凋亡细胞死亡和生长的机制 CDDO诱导的PPARgamma连接的下游阻滞。初步数据 证明CDDO诱导线粒体膜电位的丧失， 半胱天冬酶的激活。最后，我们将进行体内实验， AML的NOD/Scid模型。我们提出的机械化和 有效性研究的目的是确定CDDO作为一种新型抗白血病药物的潜力， 和抗肿瘤剂。

DESCRIPTION (PROVIDED BY APPLICANT): Treatment results for acute myeloid leukemia's (AML) have not changed for over two decades, except for the improved response rates and survival of patients with acute promyelocytic leukemia treated with all-transretinoic acid. 2-Cyano-3,12-Dioxoolean-1,9-Dien-28-Oic Acid (CDDO) is a novel triterpenoid with unique properties: it induces differentiation, inhibits cell growth and induces apoptosis in leukemia cell lines and in primary samples from patients with AML and blast transformation of CML. CDDO ligates and transcaptivates the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), which forms heterodimers with the retinoid X receptor (RXR). We here propose to extend our initial studies on the efficacy and mechanisms of CDDO activity in AML, with the goal of developing CDDO as a drug for the treatment of hematological malignancies. First, we will further investigate the growth-inhibitory effects of CDDO on primary AML and normal hematopoietic progenitors in suspension and clonogenic assay systems. Second, we will define the effects of CDDO on the transcriptional function of PPARgamma, which we found to be highly expressed in AML. Third, we will elucidate mechanisms of apoptotic cell death and growth arrest downstream from CDDO-induced PPARgamma ligation. Preliminary data demonstrate that CDDO induces loss of mitochondrial membrane potential and activation of caspases. Finally, we will conduct in vivo experiments in the NOD/Scid model of AML. The long-term goal of our proposed mechanistic and efficacy studies is to determine the potential of CDDO as a novel anti-leukemia and anti-tumor agent.