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: 10046283
• 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/10046283
• 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; 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; bronchial epithelium; cancer biomarkers; cancer cell; cancer chemoprevention; cardiovascular health; effective therapy; grape seed; improved; in vivo; indexing; inflammatory marker; insight; lung cancer cell; lung cancer prevention; lung tumorigenesis; mouse model; neoplastic cell; novel; patient derived xenograft model; 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.

葡萄籽原花青素提取物（GSE）、水飞蓟素提取物（MTE）是广泛应用的保健食品 分别促进心血管（CV）和肝胆健康的补充剂。 GSE 和 MTE 含有高含量的多酚，其结构独特，具有很强的抗氧化性能，并且每种 药物已被证明对肺癌具有抗肿瘤作用。使用组合的初步数据 GSE 和 MTE 对肺前细胞和癌细胞显示出令人兴奋的、明确的协同抗癌作用 体外。因此，我们假设口服 leucoselect 磷脂复合体 (LP)（一种 标准化 GSE 和 siliphos（一种标准化 MTE），两者均与大豆磷脂复合成植物体 提高生物利用度，协同抑制肺癌生长、侵袭，并诱导细胞凋亡 各种人类肺癌异种移植模型，通过与肺相关的机制的有利调节 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）。我们还将确定生物样本的效用，例如新鲜冷冻肺 组织匀浆，作为监测口服药物生物利用度和生物活性的替代模型系统 将这些药剂施用于靶器官。此外，组合的机械效应 将通过癌症相关、通路特异性基因表达和 microRNA 进行系统评估 (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 LP 与 siliphos 的最大耐受剂量 (MTD)、PK/PD 和抗癌作用 在小鼠模型中。将在给予不同剂量组合的裸鼠中进行剂量范围发现研究 通过口服管饲法建立 MTD。将获取血液和肺样本以确定 GSE、MTE 和 代谢物作为 GSE 和 MTE 生物利用度的替代标记。目标 1.1。测定生物活性 使用冷冻小鼠肺匀浆与人肺的新型共培养系统进行口服 LP 和 siliphos 肿瘤细胞。将通过共培养对照的肺组织匀浆来评估肺部的生物活性 （水）与药物治疗的患有人类肺癌和癌前细胞系的小鼠。不同剂量的影响 共培养细胞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 silphos 组合对各种类型癌症的抗癌作用 人类肺癌异种移植小鼠模型。根据 MTD 结果，将给予不同的剂量组合 通过口服强饲法对携带多种人类肺肿瘤异种移植物的小鼠进行长达 8 周的连续灌胃 来自每个治疗组的血浆、肺组织和肿瘤异种移植物的集合。抗癌作用 将由肿瘤生长延迟或达到最大肿瘤体积的时间以及增殖（Ki- 67) 和细胞凋亡（裂解的 caspase 3）指数，并与各种生物样本中的 GSE 和 MTE 水平相关， 参考生物活性定义生理相关水平。目标 3：识别、表征和关联 GSE联合MTE抗肺癌的分子机制。将评估机械效应 并通过比较治疗前或治疗后的生物活性，系统、全面地关联 各种样品类型，通过以下调节来测量：1) 类二十烷酸信号通路； 2) 附加标记 炎症和抗肿瘤免疫、白细胞介素 (IL)-6、IL-10、IL-12； 3) mir-19a、-19b 和 106b 水平； 4） 癌症相关的通路特异性基因表达谱； 5) 通过miRNA评估表观遗传特征 表达阵列，以及 6) 常见的癌化生物标志物，例如 PTEN、IGF2R、P53、p27、p21、p16、 FHIT 和 BIRC5。影响：研究结果将为可行性和可行性提供重要见解。 GSE和MTE联合治疗肺癌的机制作用，为临床试验铺平道路 在不久的将来，它在推进肺癌的治疗和预防方面具有巨大的潜力。