Anti-Leukemic Activity of the Novel Triterpeniod CDDO

新型三萜化合物CDDO的抗白血病活性

• 批准号: 6470779
• 负责人: MICHAEL ANDREEFF
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6470779
• 关键词: SCID mouse; acute myelogenous leukemia; antileukemic agent; antineoplastics; apoptosis; clinical research; drug interactions; drug screening /evaluation; growth inhibitors; human subject; pharmacokinetics; terpenes

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.

描述（由申请人提供）：急性髓系白血病的治疗结果 白血病 (AML) 的特征在二十多年来一直没有改变，除了改进的 急性早幼粒细胞白血病患者的缓解率和生存率 用全反式视黄酸处理。 2-氰基-3,12-二氧杂环戊烯-1,9-Dien-28-Oic 酸 (CDDO) 是一种新型三萜类化合物，具有独特的性质：它诱导 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 患者的原始样本以及原始细胞转化 慢性粒细胞白血病。 CDDO 连接并转俘获核转录因子 过氧化物酶体增殖物激活受体γ（PPARγ），形成 与类视黄醇 X 受体 (RXR) 的异二聚体。我们在此提议延长我们的 CDDO 活性在 AML 中的功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 对悬浮液中原发性 AML 和正常造血祖细胞的影响 克隆形成分析系统。其次，我们将定义 CDDO 对 PPARgamma 的转录功能，我们发现它在 反洗钱。第三，我们将阐明凋亡细胞死亡和生长的机制 CDDO 诱导的 PPARgamma 连接下游停滞。初步数据 证明 CDDO 会导致线粒体膜电位损失 半胱天冬酶的激活。最后，我们将在体内进行实验 AML 的 NOD/Scid 模型。我们提出的机制和的长期目标 功效研究旨在确定 CDDO 作为新型抗白血病药物的潜力 和抗肿瘤剂。