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: 6815356
• 负责人: JOSEPH A FONTANA
• 金额: $ 47.22万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815356
• 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.

说明书(申请人提供)：6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene羧酸(AHPN/CD437)属于一类金刚烷基维A酸(AR)，其诱导细胞凋亡的机制尚不清楚(S)。我们现在已经鉴定出一种AHPN类似4-[3-(1-adamanyly)-4-hydroxyphenyl]-3-chlorocinnamic酸(3-CI-AHPC)，它与维甲酸核受体结合，但不激活。与AHPN相比，3-C1-AHPC的毒性较低，但在体外抑制人急性髓系白血病(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的作用。此外，我们还发现3-C1-AHPC可诱导一种名为Carp-1的新蛋白的表达。我们最近在ARS中发现CARP-1是一个重要的细胞凋亡调节因子。假设：在这个方案中，我们假设3-C1-AHPC和新合成的类似物在NOD-SCID小鼠体内对人原代AML细胞的生长具有高度的抑制作用，因此是治疗AML的潜在治疗药物。此外，我们还假设3-CL-AHPC/类似物的凋亡信号是通过激活重要的转录调节因子NFkB和CARP-L介导的途径来实现的。我们的假设基于以下观察结果。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的表达可阻断3-C1-AHPC介导的细胞凋亡。我们将通过以下具体目标来证实我们的假设。目的1：合成3-c1-AHPC的新类似物。目的：证实3-C1-AHPC及其类似物在NOD-SCID小鼠体内抑制人原代AML细胞的生长，并显示出较低的毒性。目的：阐明3-CI-AHPC促进CARP-1表达和依赖于CARP-L的拓扑异构酶LIA水平降低的机制(S)。目的：探讨3-c1-AHPC激活NFkB的途径及其在细胞凋亡诱导中的作用。