Human Leukemia Growth Inhibition by a Novel Retinoid

新型类维生素A抑制人类白血病生长

• 批准号: 7087066
• 负责人: JOSEPH A FONTANA
• 金额: $ 45.85万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087066
• 关键词: DNA topoisomerases; NOD mouse; SCID mouse; acute myelogenous leukemia; analog; antineoplastics; apoptosis; biological signal transduction; cell growth regulation; clinical research; drug design /synthesis /production; enzyme inhibitors; gene expression; human subject; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; nuclear factor kappa beta; patient oriented research; pharmacokinetics; posttranslational modifications; retinoids

DESCRIPTION (provided by applicant): 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) belongs to a class of adamantyl retinoids (AR) that induce apoptosis through as yet undefined mechanism(s). We have now identified an AHPN analog 4-[3-(1-adamanyly)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-CI-AHPC), which binds to, but does not activate, the retinoic acid nuclear receptors. 3-C1-AHPC displays decreased toxicity compared to AHPN but continues to display high efficacy in inhibiting human acute myelogenous leukemia (AML) cell growth in vitro and mouse AML cells in vivo. In addition, we have found that 3-C1-AHPC induces the expression of a novel protein termed CARP-1. We recently identified CARP-1 as an important regulator of apoptosis by the ARs. Hypothesis: In this proposal we hypothesize that 3-C1-AHPC and newly synthesized analogs are highly active in inhibiting the growth of human primary AML cells in NOD-SCID mice and thus represent potential therapeutic agents in the treatment of AML. In addition, we also hypothesize that 3-CL-AHPC/analog apoptosis signaling is through its activation of the important transcriptional regulator, NFkB, and CARP-l-mediated pathways. Our hypothesis is based on the following observations. 1) 3-CI-AHPC inhibits the growth of AML cells in a syngeneic mouse model, patient derived AML cells, and human AML cell lines. 2) Inhibition of NFkB activation or inhibition of CARP-1 expression blocks 3-C1-AHPC-mediated apoptosis. We will confirm our hypothesis by conducting the following specific aims. Aim 1: Synthesize new analogs of 3-C1-AHPC. Aim 2: Demonstrate that 3-C1-AHPC and its analogs inhibit in vivo growth of human primary AML cells in NOD-SCID mice and display reduced toxicity. Aim 3: Delineate the mechanism(s) by which 3-CI-AHPC enhances CARP-1 expression and CARP-l-dependent reduced topoisomerase lIa levels. Aim 4: Delineate the pathway by which 3-C1-AHPC activates NFkB and its role in apoptosis induction.

描述（由申请人提供）：6-[3-(1-金刚烷基)-4-羟基苯基]-2-萘甲酸(AHPN/CD437)属于一类金刚烷基维A酸(AR)，其通过尚未定义的方式诱导细胞凋亡机制。我们现已鉴定出一种 AHPN 类似物 4-[3-(1-金刚烷基)-4-羟基苯基]-3-氯肉桂酸 (3-CI-AHPC)，它与视黄酸核受体结合但不激活。与 AHPN 相比，3-C1-AHPC 的毒性降低，但在体外抑制人急性髓性白血病 (AML) 细胞生长和体内抑制小鼠 AML 细胞生长方面继续表现出高效能。此外，我们还发现 3-C1-AHPC 诱导一种名为 CARP-1 的新型蛋白质的表达。我们最近发现 CARP-1 是 AR 细胞凋亡的重要调节因子。假设：在本提案中，我们假设 3-C1-AHPC 和新合成的类似物在抑制 NOD-SCID 小鼠中人原代 AML 细胞生长方面具有高度活性，因此代表了治疗 AML 的潜在治疗剂。此外，我们还假设 3-CL-AHPC/类似细胞凋亡信号传导是通过激活重要的转录调节因子 NFkB 和 CARP-1 介导的途径来实现的。我们的假设基于以下观察。 1) 3-CI-AHPC 抑制同基因小鼠模型、患者来源的 AML 细胞和人 AML 细胞系中 AML 细胞的生长。 2) 抑制 NFkB 激活或抑制 CARP-1 表达可阻断 3-C1-AHPC 介导的细胞凋亡。我们将通过实现以下具体目标来证实我们的假设。目标 1：合成 3-C1-AHPC 的新类似物。目标 2：证明 3-C1-AHPC 及其类似物可抑制 NOD-SCID 小鼠体内人原代 AML 细胞的生长，并显示出较低的毒性。目标 3：描述 3-CI-AHPC 增强 CARP-1 表达和 CARP-1 依赖性降低拓扑异构酶 IIa 水平的机制。目标 4：描述 3-C1-AHPC 激活 NFkB 的途径及其在细胞凋亡诱导中的作用。