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-亚氨烷）-4-羟基苯基] -2-萘甲苯乙烯羧酸（AHPN/CD437）属于一类adamantyl andinoi-Otiniofics（AR），通过尚未确定的机制诱导凋亡。现在，我们已经鉴定出AHPN类似物4- [3-（1-二木）-4-羟基苯基] -3-氯环酸（3-CI-AHPC），该核酸（3-CI-AHPC）与视β核受体结合但不激活。与AHPN相比，3-C1-AHPC的毒性降低，但在抑制人体内抑制人类急性粒细胞性白血病（AML）细胞生长方面的效力很高。此外，我们发现3-C1-AHPC诱导了称为鲤鱼1的新型蛋白质的表达。我们最近将Carp-1确定为ARS凋亡的重要调节剂。假设：在此提案中，我们假设3-C1-AHPC和新合成的类似物在抑制NOD-SCID小鼠中人类原代AML细胞的生长方面高度活跃，因此代表了AML治疗中潜在的治疗剂。此外，我们还假设3-CL-AHPC/模拟凋亡信号通过其激活重要的转录调节剂，NFKB和Carp-L介导的途径。我们的假设基于以下观察结果。 1）3-CI-AHPC抑制合成小鼠模型，患者衍生的AML细胞和人AML细胞系中AML细胞的生长。 2）抑制NFKB激活或抑制鲤鱼1表达阻断3-C1-AHPC介导的细胞凋亡。我们将通过执行以下特定目标来确认我们的假设。目标1：合成3-C1-AHPC的新类似物。 AIM 2：证明3-C1-AHPC及其类似物抑制了点数scID小鼠中人类原代AML细胞的体内生长，并显示出降低的毒性。 AIM 3：描述3-CI-AHPC增强Carp-1表达和鲤鱼L依赖性降低拓扑异构酶LIA水平的机制。 AIM 4：描述3-C1-AHPC激活NFKB及其在凋亡诱导中的作用的途径。