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

• 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
• 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' 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

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（由适用提供）：流行病学和动物研究已经确定自然饮食成分和补充剂会降低癌症的风险。结直肠癌（CRC）是美国恶性疾病的第二大死亡原因；死亡率约为50％。与长期感染有关的疾病，例如慢性溃疡性结肠炎（UC）和克罗恩病（CD），增加了CRC的风险。患有慢性炎症性疾病的患者的选择有限，可以降低这种风险。可以为化学预防而开发饮食构成，尤其是因为大多数人在没有严重副作用的高剂量下耐受。血清水平为1，25-二羟基维生素D（1,25d）和CRC入射之间存在逆相关性。 1,25D通过与维生素D受体（VDR）结合而功能。在慢性炎症的条件下，细胞因子释放增加了转录因子Snail1和Snail2/Slug的表达，从而导致VDR水平受到抑制，并且无法对1,25D响应。从牛奶蓟种子中分离出来的黄酮硅质素抑制了蜗牛1和sl剂量。我们建议，慢性炎症中VDR水平的snail1/slug介导的降低，可以通过与硅酸盐共同治疗，恢复1,25D的有益作用并导致有利的预后来逆转1,25D的反应。为了支持，我们表明，在HT-29人类结肠细胞中，肿瘤坏死因子 - （TNF-€）增加了蜗牛1和sl液水平，降低了VDR水平，并抑制了1,25D的抗增殖作用。硅蛋白降低了蜗牛1和sl液位，增加了VDR水平，逆转TNF-®对SNAIL1，SLUG和VDR以及细胞增殖的影响，并恢复1,25D无反应细胞中维生素D反应元素介导的启动子活性。硅酸盐素和1,25D协同抑制TNF -tnf-诱导的细胞增殖。我们的长期目标是确定硅酸盐素和1,25D是否 类似物以化学预防剂协同起作用，以防止在慢性炎症条件下CRC的发展。我们将通过追求这些特定目标来检验我们的假设。 1）1,25D信号传导在硅蛋白介导的受保护作用中的作用将使用细胞增殖，迁移和侵袭作为读数来评估炎性细胞因子介导的结肠细胞损伤； 2）将在AOM/DSS（偶氮甲烷/脱氧硫酸钠硫酸钠）小鼠模型中评估硅蛋白 + EB1089（非高流血1,25D模拟）方案对注射和肿瘤发生的影响。这些研究将为未来的机械和翻译研究奠定基础，旨在开发一种1,25D类似物 +硅酸盐素治疗方案，以防止患有慢性炎症患者的CRC。

项目成果

Restoration of the anti-proliferative and anti-migratory effects of 1,25-dihydroxyvitamin D by silibinin in vitamin D-resistant colon cancer cells.

• DOI: 10.1016/j.canlet.2015.03.042
• 发表时间: 2015-07-01
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Bhatia, Vandanajay;Falzon, Miriam
• 通讯作者: Falzon, Miriam