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Development of a Silibinin/Vitamin D Regimen for Colon Cancer Prevention

开发用于预防结肠癌的水飞蓟宾/维生素 D 疗法

基本信息

批准号：
8829794
负责人：
MIRIAM FALZON
金额：
$ 7.75万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
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：
2014-04-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829794
关键词：
1,25 (OH) vitamin D 25-hydroxyvitamin D Accounting Address Adenocarcinoma Adverse effects Animals Appearance Azoxymethane Binding Cause of Death Cell Culture Techniques Cell Proliferation Cells Chemoprevention Chemopreventive Agent Chronic Colon Colon Carcinoma Crohn&apos s disease Development Diabetes Mellitus Dietary Component Dietary Fiber Disease Dose Epidemiology Epithelial Cells Failure Flavonolignans Food Foundations Future Goals HT29 Cells Health Heart Diseases Human Hypercalcemia In Vitro Incidence Individual Inflammation Inflammatory Inflammatory Bowel Diseases Large Intestine Carcinoma Malignant - descriptor Malignant Neoplasms Mediating Micronutrients Milk Thistle Monitor Outcome Patients Phenotype Plants Play Property Regimen Reporting Repression Risk Role Seeds Serum Signal Transduction Site Snails Sodium Dextran Sulfate Stroke Testing Treatment Efficacy Tumor Necrosis Factor-alpha Tumor Promotion Ulcerative Colitis Up-Regulation Vitamin D Vitamin D Analog Vitamin D Response Element Vitamin D3 Receptor analog animal data cancer prevention cancer risk carcinogenesis cell injury cytokine design dietary constituent dietary supplements fruits and vegetables in vivo Model migration mortality mouse model novel outcome forecast prevent promoter protective effect receptor downregulation receptor expression research study silibinin slug transcription factor translational study tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Epidemiologic and animal studies have established that natural dietary components and supplements reduce cancer risk. Colorectal carcinoma (CRC) is the second most common cause of death from malignant disease in the US; the mortality rate is ~50%. Diseases associated with long-term inflammation of the colon, such as chronic ulcerative colitis (UC) and Crohn's disease (CD), increase the risk for CRC. Patients with chronic inflammatory disease have limited options to reduce this risk. Dietary constituents can be developed for chemoprevention, especially since most are tolerated at high doses without serious side-effects. An inverse correlation exists between serum levels of 1, 25-dihydroxyvitamin D (1,25D) and CRC incidence. 1,25D functions by binding to the vitamin D receptor (VDR). In conditions of chronic inflammation, cytokine release increases expression of the transcription factors Snail1 and Snail2/Slug, leading to suppressed VDR levels and failure to respond to 1,25D. The flavonolignan silibinin, isolated from milk thistle seeds, suppresses Snail1 and Slug levels. We propose that Snail1/Slug-mediated decrease in VDR levels in chronic inflammation, accounting for failure to respond to 1,25D, can be reversed by co-treating with silibinin, restoring the beneficial effects of 1,25D and leading to a favorable prognosis. In support, we show that, in HT-29 human colon cells, tumor necrosis factor-¿ (TNF-¿) increases Snail1 and Slug levels, decreases VDR levels, and suppress 1,25D's anti-proliferative effects. Silibinin decreases Snail1 and Slug levels, increases VDR levels, reverses the TNF-¿ effects on Snail1, Slug and VDR and on cell proliferation, and restores Vitamin D Response Element-mediated promoter activity in 1,25D-unresponsive cells. Silibinin and 1,25D synergistically inhibit TNF-¿-induced cell proliferation. Our long-term goal is to determine if silibinin and 1,25D analogs function synergistically as chemopreventive agents to prevent CRC development in conditions of chronic inflammation. We will test our hypothesis by pursuing these Specific Aims. 1) The role of 1,25D signaling in the silibinin-mediated protective effects against inflammatory cytokine-mediated colon cell damage will be assessed using cell proliferation, migration and invasion as readouts; and 2) the effect of a silibinin + EB1089 (non-hypercalcemic 1,25D analog) regimen on inflammation and tumorigenesis will be evaluated in the AOM/DSS (azoxymethane/dextran sodium sulfate) mouse model. These studies will lay the foundation for future mechanistic and translational studies aimed at developing a 1,25D analogs + silibinin regimen to prevent CRC in patients with chronic inflammation.

描述（由申请人提供）：流行病学和动物研究已经确定，天然膳食成分和补充剂可以降低癌症风险。结直肠癌（CRC）是美国恶性疾病的第二大常见死因;死亡率约为50%。与结肠长期炎症相关的疾病，如慢性溃疡性结肠炎（UC）和克罗恩病（CD），增加了CRC的风险。慢性炎症性疾病患者减少这种风险的选择有限。饮食成分可以被开发用于化学预防，特别是因为大多数在高剂量下是耐受的，没有严重的副作用。血清1，25-二羟维生素D（1，25 D）水平与结直肠癌发病率呈负相关。1，25 D通过与维生素D受体（VDR）结合发挥作用。在慢性炎症条件下，细胞因子释放增加转录因子Snail 1和Snail 2/Slug的表达，导致VDR水平抑制和对1，25 D的反应失败。从奶蓟种子中分离出的黄酮木脂体水飞蓟宾抑制蜗牛1和鼻涕虫水平。我们提出，Snail 1/Slug介导的慢性炎症中VDR水平的降低，解释了对1，25 D的反应失败，可以通过与水飞蓟宾共同治疗来逆转，恢复1，25 D的有益作用并导致良好的预后。作为支持，我们表明，在HT-29人结肠细胞中，肿瘤坏死因子-<$（TNF-<$）增加Snail 1和Slug水平，降低VDR水平，并抑制1，25 D的抗增殖作用。水飞蓟宾降低Snail 1和Slug水平，增加VDR水平，逆转TNF-α对Snail 1、Slug和VDR以及细胞增殖的影响，并恢复1，25 D无反应细胞中维生素D反应元件介导的启动子活性。水飞蓟宾和1，25 D协同抑制TNF-γ诱导的细胞增殖。我们的长期目标是确定水飞蓟宾和1，25 D 类似物作为化学预防剂协同作用以预防慢性炎症条件下的CRC发展。我们将通过追求这些具体目标来检验我们的假设。1)将使用细胞增殖、迁移和侵袭作为读数来评估1，25 D信号传导在水飞蓟宾介导的针对炎性丝氨酸介导的结肠细胞损伤的保护作用中的作用;和2）将在AOM/DSS（氧化偶氮甲烷/葡聚糖硫酸钠）小鼠模型中评估水飞蓟宾+EB 1089（非高钙蛋白酶1，25 D类似物）方案对炎症和肿瘤发生的作用。这些研究将为未来的机制和翻译研究奠定基础，旨在开发1，25 D类似物+水飞蓟宾方案，以预防慢性炎症患者的CRC。