Combinations of Grape Seed and Milk Thistle Extracts Against Lung

葡萄籽和水飞蓟提取物的组合对肺的作用

• 批准号: 9562906
• 负责人: JENNY T MAO
• 金额: --
• 依托单位: ALBUQUERQUE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9562906
• 关键词: A549; Aftercare; Antineoplastic Agents; Antioxidants; Apoptosis; Apoptotic; BIRC5 gene; Biological Availability; Biological Markers; Biological Models; Blood; CASP3 gene; Cancer Etiology; Cancer cell line; Cardiovascular system; Cell Line; Cessation of life; Chemical Structure; Chemopreventive Agent; Cleaved cell; Clinical; Clinical Trials; Coculture Techniques; Collection; Complex; Crude Extracts; Cultured Cells; Data; Dose; Drug Kinetics; Eicosanoids; Epigenetic Process; Epithelial Cells; Expression Profiling; FHIT gene; Food Supplements; Freezing; Future; Gene Chips; Gene Expression; Growth; Health; Health Food; Hepatobiliary; Human; IGF2R gene; In Vitro; Induction of Apoptosis; Inhibition of Cell Proliferation; Interleukin-10; Interleukin-12; Interleukin-6; Lead; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Maximum Tolerated Dose; Measures; Mediating; MicroRNAs; Milk Thistle; Milk thistle extract; Molecular; Monitor; Mus; Nude Mice; Oral; Oral Administration; Organ; Outcome; PTEN gene; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phospholipids; Physiological; Plasma; Pre-Clinical Model; Premalignant Cell; Procyanidins; Property; Reporting; Sampling; Signal Pathway; Silymarin; Site; Standardization; Structure; Structure of parenchyma of lung; Surrogate Endpoint; Surrogate Markers; System; TP53 gene; Testing; Time; Translating; Tumor Immunity; Tumor Volume; Veterans; Water; Xenograft Model; Xenograft procedure; anti-cancer; base; cancer biomarkers; cancer cell; cancer chemoprevention; cardiovascular health; effective therapy; grape seed; improved; in vivo; indexing; inflammatory marker; insight; lung cancer prevention; lung tumorigenesis; mouse model; neoplastic cell; novel; pharmacokinetics and pharmacodynamics; polyphenol; predicting response; soy; treatment duration; treatment group; treatment response; treatment strategy; tumor growth; tumor xenograft

Grape seed procyanidin extract (GSE), and milk thistle silymarin extract (MTE) are widely used health food supplements to promote cardiovascular (CV) and hepatobiliary health, respectively. Both GSE and MTE contain high levels of polyphenols that are structurally distinct with strong antioxidant properties, and each agent has been shown to exert antineoplastic effects against lung cancer. Preliminary data using combinations of GSE and MTE shows exciting, unequivocal synergistic anticancer effects against lung pre- and cancer cells in vitro. We therefore hypothesize that oral administration of combinations of leucoselect phytosome (LP), a standardized GSE, and siliphos, a standardized MTE, both complexed with soy phospholipids into phytosomes to enhance bioavailability, will synergistically inhibit lung cancer growth, invasion, and induce apoptosis in various human lung cancer xenograft models, via favorable modulations of mechanisms associated with lung tumorigenesis/promotion. To test these hypotheses, we will determine their pharmacokinetics (PK) and pharmacodynamics (PD). We will also determine the utility of biospecimens, such as snap, fresh frozen lung tissue homogenates, as surrogate model systems to monitor the bioavailability and bioactivity of oral administration of these agents to the target organ. Furthermore, the mechanistic effects of the combinations will be assessed systematically with cancer relevant, pathway specific gene expressions and microRNA (miRNA) real time PCR arrays, and correlated to functional significance. Three specific aims are proposed: Aim 1: To determine the maximum tolerated dose (MTD), PK/PD, and anti-cancer effects of LP with siliphos in murine models. A dose range finding study will be conducted in nude mice given varying dose combinations via oral gavage to establish MTD. Blood and lung samples will be obtained to determine PK of GSE, MTE and metabolites as surrogate markers of bioavailability of GSE and MTE. Aim 1.1. To determine the bioactivity of oral LP and siliphos using a novel co-culture system of frozen mouse lung homogenates with human lung neoplastic cells. Bioactivity in the lungs will be assessed by co-culturing lung tissue homogenates from control (water) vs. drug treated mice with human lung cancer and precancerous cell lines. The effects of varying dose combinations on proliferation and apoptosis in co-cultured cells will be correlated to GSE, MTE and metabolites levels. Aim 2: To determine the anti-cancer effects of combinations of LP and siliphos on various types of human lung cancer xenograft mouse models. Based on MTD findings, varying dose combinations will be given via oral gavage to mice bearing a variety of human lung tumor xenografts for up to 8 weeks with serial collections of plasma, lung tissues and tumor xenografts from each treatment group. The anticancer effects will be determined by tumor growth delay or time to reach maximum tumor volume, as well as proliferation (Ki- 67) and apoptotic (cleaved caspase 3) indices, and correlated to GSE & MTE levels in various biospecimens, to define physiologically relevant levels in reference to bioactivity. Aim 3: To identify, characterize and correlate the molecular mechanisms of GSE with MTE against lung cancer. The mechanistic effects will be assessed and correlated systematically and comprehensively, by comparing the bioactivity pre- or post treatment, in various sample types, as measured by modulations of: 1) eicosanoid signaling pathways; 2) additional markers of inflammations and anti-tumor immunity, interleukin (IL)-6, IL-10, IL-12; 3) mir-19a, -19b and 106b levels; 4) cancer relevant, pathway specific gene expression profiles; 5) epigenetic profiles assessed by miRNA expression array, and 6) common biomarkers of cancerization such as PTEN, IGF2R, P53, p27, p21, p16, FHIT, and BIRC5. IMPACT: Findings from the study will provide important insights into the feasibility and mechanistic effects of combinations of GSE and MTE against lung cancer, and pave the way for clinical trials in the near future, with enormous potential in advancing the treatment and prevention of lung cancer.

葡萄种子procyanidin提取物（GSE）和牛奶蓟水莲蛋白提取物（MTE）广泛使用的健康食品 补充剂分别促进心血管（CV）和肝胆健康。 GSE和MTE都 含有高水平的多酚在结构上具有强大的抗氧化特性，并且 已证明药物对肺癌发挥抗肿瘤作用。使用组合的初步数据 GSE和MTE显示出令人兴奋的，明确的协同抗癌对肺前和癌细胞的作用 体外。因此，我们假设口服链状植物体的组合（LP），A 标准化的GSE和Siliphos是标准化的MTE，都将大豆磷脂复合成植物体 为了增强生物利用度，会协同抑制肺癌的生长，侵袭和诱导凋亡 各种人类肺癌异种移植模型，通过与肺有关的机制的有利调制 肿瘤发生/促进。为了检验这些假设，我们将确定它们的药代动力学（PK）和 药效学（PD）。我们还将确定生物测量的实用性，例如快照，新鲜的冷冻肺 组织匀浆，作为替代模型系统，以监测口服的生物利用度和生物活性 将这些试剂施用到目标器官。此外，组合的机械效应 将系统地评估与癌症相关，途径特定基因表达和microRNA的评估 （miRNA）实时PCR阵列，并与功能意义相关。提出了三个具体目标： 目标1：确定最大耐受剂量（MTD），PK/PD和LP与Siliphos的抗癌作用 在鼠模型中。给定不同剂量组合的裸小鼠将进行剂量范围的研究研究 通过口服饲料建立MTD。将获得血液和肺样本，以确定GSE，MTE和MTE的PK 代谢物作为GSE和MTE的生物利用度的替代标记。目标1.1。确定 口服LP和Siliphos使用新型的共培养系统与人肺的冷冻小鼠肺匀浆 肿瘤细胞。肺中的生物活性将通过对照共同培养肺组织匀浆来评估 （水）与药物治疗的小鼠患有人肺癌和癌前细胞系。不同剂量的影响 共培养细胞中增殖和凋亡的组合将与GSE，MTE和代谢物相关 水平。目标2：确定LP和Siliphos组合对各种类型的抗癌作用 人肺癌异种移植小鼠模型。根据MTD的发现，将给出不同的剂量组合 通过口服口服对携带各种人肺肿瘤异种移植的小鼠长达8周 来自每个治疗组的血浆，肺组织和肿瘤异种移植的收集。抗癌作用 将取决于肿瘤生长延迟或达到最大肿瘤体积的时间以及增殖（Ki- 67）和凋亡（裂解的caspase 3）指数，并与各种生物测量中的GSE和MTE水平相关， 定义有关生物活性的生理相关水平。目标3：识别，表征和关联 与MTE抗肺癌的GSE的分子机制。机械效应将被评估 并通过比较生物活性前或治疗后的生物活性，并在 各种样品类型，如以下调制测量：1）类类样品信号通路； 2）其他标记 炎症和抗肿瘤免疫，白介素（IL）-6，IL-10，IL-12； 3）miR -19a，-19b和106b级别； 4） 癌症相关，途径特异性基因表达谱； 5）由miRNA评估的表观遗传特征 表达阵列和6）癌化的常见生物标志物，例如PTEN，IGF2R，p53，p27，p21，p16， fhit和Birc5。影响：研究结果将为可行性和 GSE和MTE组合对肺癌的机械作用，并为临床试验铺平道路 在不久的将来，在推进肺癌的治疗和预防方面具有巨大的潜力。