Anti-Leukemic Activity of the Novel Triterpeniod CDDO

描述(申请人提供)：急性髓系白血病的治疗结果 白血病(AML)20多年来没有变化，除了 急性早幼粒细胞白血病患者的有效率和存活率 用全反式维甲酸治疗。2-氰基-3，12-二氧杂环烯-1，9-二烯-28-OIC 酸(CDDO)是一种新的三萜类化合物，具有独特的性质：它诱导 分化，抑制细胞生长，诱导白血病细胞凋亡 急性髓系白血病和急性髓系白血病患者的原始样本中 CML。CDDO连接并转译核转录因子 过氧化物酶体增殖物激活受体γ(PPARGamma)，它形成 与维甲酸X受体(RXR)的异二聚体。我们在此提议延长我们的 CDDO活性对急性髓系白血病疗效及机制的初步研究 CDDO作为治疗血液病药物的目标 恶性肿瘤。首先，我们将进一步研究其生长抑制作用。 CDDO对原代AML和正常造血祖细胞悬液中的作用 克隆检测系统。其次，我们将定义CDDO对 PPARGamma的转录功能，我们发现它在 AML。第三，我们将阐明细胞凋亡的死亡和生长机制。 CDDO诱导的PPARγ连接的下游停滞。初步数据 证明CDDO可导致线粒体膜电位的丧失和 半胱氨酸酶的激活。最后，我们将在体内进行实验 急性髓系白血病的NOD/SCID模型。我们提议的机械化和 疗效研究是为了确定CDDO作为一种新的抗白血病药物的潜力 和抗肿瘤药物。

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.