Modulation of the S100A9/CD33 Pathway by the Flavonoids ICA and ICT on the Tumor

类黄酮 ICA 和 ICT 对肿瘤中 S100A9/CD33 通路的调节

基本信息

批准号：
9122359
负责人：
ERIKA Adriana EKSIOGLU
金额：
$ 9.11万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9122359
关键词：
Accounting Affect American Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Architecture Basic Science Binding Biological Cancer Center Cancer Immunology Science Cell physiology Cells Clinic Clinical Computer Simulation Data Development Disease Disease Progression Down-Regulation Dysmyelopoietic Syndromes Epimedium Flavones Flavonoids Future Goals Health Hematological Disease Human Immune Immune system Immunosuppression In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Institution Knock-in Lead Ligands Ligation Link MAP Kinase Gene MAPK14 gene Maintenance Malignant - descriptor Malignant Neoplasms Manuscripts Mediating Mediator of activation protein Mentored Research Scientist Development Award Mentors Mentorship Modeling Molecular Molecular Target Mus Myelogenous NF-kappa B NR0B2 gene Names Natural Immunity One-Step dentin bonding system Pathway interactions Pattern Pharmaceutical Preparations Phosphoric Monoester Hydrolases Plants Play Production Property Publishing Research Research Design Research Personnel Role S100A8 gene S100A9 gene STAT3 gene Signal Pathway Signal Transduction Specificity Suppressor-Effector T-Lymphocytes Surface Therapeutic Training Translational Research Tumor Burden Up-Regulation Venezuelan Viagra Work Xenograft Model adaptive immunity angiogenesis antitumor effect cancer cell cancer immunotherapy cancer therapy career career development clinical application cytotoxic cytotoxicity faculty research horny goat weed improved in vivo inflammatory marker inhibitor/antagonist insight knockout animal mouse model neoplastic cell new therapeutic target novel phosphodiesterase V post-doctoral training receptor research facility research study sildenafil success synthetic drug therapeutic target tumor tumor growth tumor microenvironment tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Modulation of the S100A9/CD33 pathway by the flavonoids ICA and ICT on the tumor microenvironment Background: Myeloid-derived suppressive cells are a recently derived component of the tumor microenvironment that has been determined to have a pivotal role in the maintenance and progression of cancer. These cells contribute to the upregulation of inflammatory correlated with tumor progression such as MRP8/9. Flavonoids are a group of polyphenolic compounds, commonly found on plants with many biological abilities that could prove useful in the battle against disease including anti-inflammatory, antioxidant and, more recently, anti-tumorigenic properties. Those obtained from Herba Epimedii, specifically its active compound icariin (ICA) and a derivative named 3, 5, 7-Trihydroxy-4'-methoxy-8-(3-hydroxy-3- methylbutyl)-flavone (ICT), have been shown to have strong immunomodulatory as well as anti-tumorigenic effects. Hypothesis and objective: We have recently shown that both of these compounds have potent modulatory effects that involve the downregulation of MDSC and MRP8/14 from the tumor microenvironment as well as the deactivation of STAT3, NF-kB and MAPK pathway components, cytotoxicity of tumor cells in vitro and the reduction of tumor burden in a mice model of cancer. While strides have been made in recognizing the role of these compounds on their therapeutic potential against cancer, their mechanisms of action is poorly understood. In particular we hypothesize that the effect on MDSC is linked to the inhibition of PDE5 just as seen with synthetic drugs like Viagra. We also hypothesize that the effect of these compounds on inflammatory pathways is mediated by the activation and perhaps upregulation of phosphatases, in particular PP2A as has been suggested previously. This particular effect might be linked to the direct cytotoxic effect of thes compounds on cancer cells. It is also possible that in vivo these drugs could have a direct impact on the architecture of the tumor microenvironment that lead to its destabilization and the inhibition of tumor growth. Therefore the study of the mechanisms involved in the modulation of MDSC and inflammatory markers linked to cancer by ICA and ICT would provide the insight to bring these compounds one step closer to the clinic for future therapeutical applications. Specific aims: Aim1: To understand the role of PDE5 inhibition on ICA/ICT action. Aim 2: To investigate the role of phosphatases on the deactivation of pro-inflammatory mediators by ICA and ICT. Aim 3: To study the regulatory mechanisms of ICA/ICT on the in vivo tumor microenvironment. Study design: For aim 1, we will first continue in silico modeling that demonstrates the specificities of the binding of ICT with PDE5. We will continue our assessment of this binding with mechanistic in vitro studies and determine if the mechanism is similar to that of other PDE5 inhibitors like sildenafil, our control. We will also determine if some of the effect of PDE5 inhibition affect tumor cells as well. For aim 2, we will determine the role of phosphatases on the deactivation of key pro-inflammatory pathways NF-kB, Akt, ERK, p38, and Stat3. Are PP2A and SHP1 the only phosphatases? Is there a specific type of phosphatases that gets activated by ICA and ICT. For aim 3, we will do in vivo studies to understand the role of these pathways and the importance each one of them plays in the modulatory role of ICA and ICT.

描述（由申请人提供）：类黄酮ICA和ICT对S100A9/CD33途径的调节对肿瘤微环境的背景：髓样衍生的抑制细胞是最近衍生的肿瘤微环境的成分，已被确定在癌症的维持和进展中具有重要的作用。这些细胞有助于与肿瘤进展（例如MRP8/9）相关的炎症性上调。类黄酮是一组多酚化合物，通常在具有许多生物学能力的植物上发现，这些能力可能在抗疾病的战斗中有用，包括抗炎，抗氧化剂以及最近，抗肿瘤性特性。从HERBA EPIMEDII获得的那些，特别是其活性化合物ICARIIN（ICA）和一个衍生物，称为3、5、7-三羟基-4'-甲氧基-8-（3-羟基-3-甲基丁基）-Flavone（ICT） - 已显示出强烈的免疫原子化效果，并具有强烈的Immunomodulation and anti-tumerig， Hypothesis and objective: We have recently shown that both of these compounds have potent modulatory effects that involve the downregulation of MDSC and MRP8/14 from the tumor microenvironment as well as the deactivation of STAT3, NF-kB and MAPK pathway components, cytotoxicity of tumor cells in vitro and the reduction of tumor burden in a mice model of cancer.尽管在认识到这些化合物对癌症治疗潜力的作用方面取得了进步，但对它们的作用机理的理解很少。特别是我们假设对MDSC的影响与PDE5的抑制有关，就像伟哥这样的合成药物所见。我们还假设，这些化合物对炎症途径的影响是由磷酸酶的激活和上调介导的，尤其是PP2A，尤其是以前建议的。这种特殊作用可能与这些化合物对癌细胞的直接细胞毒性作用有关。在体内，这些药物可能会直接影响肿瘤微环境的结构，从而导致其不稳定和抑制肿瘤生长。因此，对ICA和ICT与癌症相关的MDSC调节和炎症标志物调节的机制的研究将为您提供洞察力，以使这些化合物更靠近诊所，以实现未来的治疗应用。具体目的：AIM1：了解PDE5抑制对ICA/ICT行动的作用。目的2：研究磷酸酶对ICA和ICT促炎性介质失活的作用。目标3：研究ICA/ICT的调节机制在体内肿瘤微环境中。研究设计：对于AIM 1，我们将首先继续进行计算机建模，以证明ICT与PDE5的结合的特异性。我们将继续评估与机械体外研究结合的评估，并确定该机制是否类似我们控制的其他PDE5抑制剂，例如西地那非。我们还将确定PDE5抑制作用的某些作用是否也影响肿瘤细胞。对于AIM 2，我们将确定磷酸酶在关键促炎途径NF-KB，AKT，ERK，P38和STAT3失活方面的作用。 PP2A和SHP1是唯一的磷酸酶吗？是否有特定类型的磷酸酶被ICA和ICT激活。对于AIM 3，我们将进行体内研究，以了解这些途径的作用以及每个途径的重要性在ICA和ICT的调节作用中发挥作用。