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

描述（由申请人提供）：类黄酮ICA和ICT对肿瘤微环境中S100A9/CD33通路的调节背景：髓源性抑制细胞是肿瘤微环境中最近衍生的成分，已被确定在癌症的维持和进展中起关键作用。这些细胞有助于与肿瘤进展相关的炎症的上调，如MRP8/9。黄酮类化合物是一组多酚类化合物，通常存在于具有多种生物能力的植物中，这些能力可能被证明对对抗疾病有用，包括抗炎、抗氧化以及最近的抗肿瘤特性。从淫羊藿中提取的活性物质，特别是淫羊藿苷（ICA）及其衍生物3,5,7 -三羟基-4′-甲氧基-8-（3-羟基-3-甲基丁基）-黄酮（ICT），已被证明具有很强的免疫调节和抗肿瘤作用。假设和目的：我们最近发现，这两种化合物都具有强大的调节作用，包括肿瘤微环境中MDSC和MRP8/14的下调，STAT3、NF-kB和MAPK通路组分的失活，体外肿瘤细胞的细胞毒性和癌症小鼠模型中肿瘤负荷的减轻。虽然在认识到这些化合物在抗癌治疗潜力方面的作用方面取得了长足的进步，但它们的作用机制却知之甚少。特别是，我们假设对MDSC的影响与PDE5的抑制有关，就像伟哥等合成药物一样。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可能的上调介导的，特别是PP2A，正如之前所建议的那样。这种特殊的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，这些药物也可能对肿瘤微环境的结构产生直接影响，导致其不稳定并抑制肿瘤生长。因此，通过ICA和ICT对MDSC和与癌症相关的炎症标志物的调节机制的研究将为这些化合物在未来的治疗应用中更接近临床提供见解。目的1：了解PDE5抑制在ICA/ICT作用中的作用。目的2：探讨磷酸酶在ICA和ICT促炎介质失活中的作用。目的3：研究ICA/ICT对体内肿瘤微环境的调控机制。研究设计：对于目标1，我们将首先继续进行计算机建模，以证明ICT与PDE5结合的特异性。我们将继续通过体外机制研究来评估这种结合，并确定其机制是否与之相似

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.