Human Leukemia Growth Inhibition by a Novel Retinoid

描述（由申请人提供）：6-[3-（1-金刚烷基）-4-羟基苯基]-2-萘羧酸（AHPN/CD437）属于一类金刚烷基类维甲酸（AR），其诱导细胞凋亡的机制尚未明确。我们现在已经确定了一种AHPN类似物4-[3-（1-金刚烷基）-4-羟基苯基]-3-氯辛酸（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，但在体外和体内抑制人类急性髓性白血病（AML）细胞和小鼠AML细胞的生长方面继续显示出高效率。此外，我们还发现3-C1-AHPC诱导了一种名为CARP-1的新蛋白的表达。我们最近发现CARP-1是ARs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和新合成的类似物对NOD-SCID小鼠的人原发性AML细胞生长具有高度活性，因此代表了治疗AML的潜在治疗药物。此外，我们还假设3-CL-AHPC/模拟细胞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。我们的假设是基于以下观察。1) 3-CI-AHPC在同基因小鼠模型、患者源性AML细胞和人类AML细胞系中抑制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。我们将通过实施以下具体目标来证实我们的假设。目的1：合成新的3-C1-AHPC类似物。目的2：证明3-C1-AHPC及其类似物抑制NOD-SCID小鼠体内人原代AML细胞的生长，并显示降低毒性。目的3：描述3- ci - ahpc增强CARP-1表达和CARP-1依赖性降低的拓扑异构酶lIa水平的机制。目的4：描述3-C1-AHPC激活NFkB的途径及其在诱导凋亡中的作用。

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.