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: 10421238
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421238
• 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; 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 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)和水飞蓟素提取物(MTE)是广泛使用的保健食品 分别促进心血管(CV)和肝胆健康的补充剂。GSE和MTE 含有高水平的多酚，这些多酚在结构上是不同的，具有很强的抗氧化性能，而且每种 该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对肺癌前体细胞和癌细胞显示出令人兴奋的、明确的协同抗癌作用 在试管中。因此，我们假设口服亮氨酸选择植物小体(LP)、A的组合。 标准化GSE和siliphos是一种标准化的MTE，两者都与大豆磷脂络合形成植体 为了提高生物利用度，是否会协同抑制肺癌的生长、侵袭和诱导细胞凋亡 通过对肺相关机制的有利调控，建立多种人肺癌异种移植模型 肿瘤发生/促进。为了验证这些假说，我们将确定它们的药代动力学(PK)和 药效学(PD)。我们还将确定生物标本的效用，如Snap、新鲜冰冻肺 组织匀浆作为监测口腔生物利用度和生物活性的替代模型系统 给靶器官注射这些药物。此外，组合的机械效应 将通过与癌症相关的、途径特定的基因表达和microRNA进行系统评估 (MiRNA)实时聚合酶链式反应阵列，并与功能意义相关。提出了三个具体目标： 目的1：测定含硫磷脂磷的最大耐受量(MTD)、pK/pD及抗癌作用 在小鼠模型中。将在给予不同剂量组合的裸鼠身上进行剂量范围发现研究 经口灌胃建立MTD模型。将采集血液和肺样本，以确定GSE、MTE和 代谢物作为GSE和MTE生物利用度的替代标志物。目标1.1。测定…的生物活性 应用冷冻小鼠肺匀浆与人肺共培养体系的口服LP和siliphos 肿瘤细胞。肺中的生物活性将通过与对照肺组织匀浆共培养来评估。 (水)与药物治疗的小鼠人类肺癌和癌前病变细胞系。不同剂量的影响 共培养细胞增殖和凋亡的组合将与GSE、MTE和代谢产物相关 级别。目的2：测定脂多糖和硫磷联合应用对不同类型肿瘤的抗癌作用。 人肺癌异种移植小鼠模型。根据MTD结果，将给出不同的剂量组合 连续灌胃给荷人肺癌移植瘤小鼠长达8周 收集各治疗组的血浆、肺组织和肿瘤移植瘤。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caspase 3)指数，并与不同生物样本中GSE和MTE水平相关， 定义与生物活性有关的生理水平。目标3：确定、描述和关联 GSE联合MTE抗肺癌的分子机制。将对机械效应进行评估 并通过比较治疗前和治疗后的生物活性，系统和全面地关联 不同的样本类型，通过以下调制来测量：1)二十烷类信号通路；2)附加标记 炎症和抗肿瘤免疫：IL-6、IL-10、IL-12；3)mir-19a、-19b和106b水平；4) 癌症相关、途径特异性基因表达谱；5)用miRNA评估表观遗传学谱 6)常见的癌变生物标志物，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联合抗肺癌的作用机制，为临床试验铺路 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。