Sulforaphane: A Dietary HDAC Inhibitor and Prevention of DCIS Progression

萝卜硫素：膳食 HDAC 抑制剂和预防 DCIS 进展

• 批准号: 7588377
• 负责人: JACKILEN SHANNON
• 金额: $ 13.91万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588377
• 关键词: Address; Adjuvant Chemotherapy; Adjuvant Therapy; Adverse effects; Alternative Therapies; American; Animal Model; Apoptosis; Attention; Biological Markers; Blood; Blood Cells; Breast Cancer Cell; Breast Cancer Model; Cancer Patient; Cancerous; Caspase; Cell Proliferation; Chemopreventive Agent; Chemoprotection; Chemoprotective Agent; Clinical; Clinical Research; Colon Carcinoma; Consumption; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Diet; Dietary Assessment; Disease; Disease Progression; Dose; Ductal; Effectiveness; Epidemiologic Studies; Epigenetic Process; Evaluation; Event; Food; Foundations; Future; Gene Silencing; Grouping; Growth; Health Care Costs; Histone Acetylation; Histone H4; Histones; Human; Human Volunteers; In Vitro; Intake; Intervention Studies; Intraductal Hyperplasia; Liquid substance; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Measurable; Medical; Methods; Nature; Nipples; Noninfiltrating Intraductal Carcinoma; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Penetration; Phytochemical; Plasma; Population Study; Prevention; Prostate; Qualifying; Quality of life; Radiation therapy; Recommendation; Reporting; Research; Risk; Role; Staging; Structure; Sulforaphane; Supplementation; Techniques; Testing; Tissues; Toxic effect; Tumor Suppressor Genes; Urine; Woman; base; breast cancer diagnosis; cancer cell; cancer prevention; combat; cruciferous vegetable; effective therapy; healthy volunteer; improved; in vivo; inhibitor/antagonist; interest; malignant breast neoplasm; novel; outcome forecast; peripheral blood; prevent; promoter; public health relevance; randomized placebo controlled trial; success; therapy resistant; tumor growth; tumorigenesis; tumorigenic; urinary

DESCRIPTION (provided by applicant): Sulforaphane, A Dietary HDAC Inhibitor, and Prevention of DCIS Progression Project Summary Significant advances in diagnosis and medical management of ductal carcinoma in situ (DCIS) have markedly reduced disease progression and improved long-term survival. However, there are limited medically accepted options for neo-adjuvant therapy to improve surgical success; though it is common for women to seek alternative therapies in an attempt to improve outcome. Hence, there is a need for scientifically directed evaluation of dietary substances that may effectively inhibit the progression of DCIS. Inhibitors of histone deacetylases (HDAC) have generated considerable recent interest as novel chemoprotective agents because they target epigenetic events that can occur at various stages of cancer development. Pharmacological HDAC inhibitors have anti- cancer effects in breast cancer cells both in vitro and in vivo. However, the adverse effects of these agents make them undesirable for long-term use in women with pre- invasive disease (DCIS). Sulforaphane (SFN), a phytochemical found in cruciferous vegetables, has received recent attention as a potential chemopreventive agent, yet its precise mechanism of action remains unclear. Based on the studies with dietary HDAC inhibitors in prostate and colon cancer cells, and in healthy volunteers, we propose to examine these associations in a breast cancer model and test the effectiveness of supplemental SFN intake in improving biomarkers for prognosis and in altering HDAC activity in DCIS patients. This DIETARY approach to cancer prevention has several advantages over conventional pharmacological HDAC inhibitors, including less toxicity and ease of administration. The use of SFN as a chemopreventive approach is significant because of its relatively non-toxic nature and multiple biologically relevant anti-tumorigenic activities. PUBLIC HEALTH RELEVANCE: Significant advances in the diagnosis and medical management of ductal carcinoma in situ (DCIS) have markedly reduced disease progression and improved long-term survival. However, despite overall good outcomes, the effective treatment of DCIS still requires surgery and radiation therapy, and we need better methods of preventing disease progression. There are limited medically accepted options for neo-adjuvant therapy to improve surgical success, and the typical neo-adjuvant chemotherapy given for invasive disease does not impact DCIS outcome due, in part, to decreased penetration into the ductal space. Thus, it is common for women to seek alternative therapies in an attempt to improve outcome. Hence, there is a need for scientifically directed evaluation of dietary substances that may effectively inhibit the progression of DCIS. A number of epidemiologic studies have reported an inverse association between cruciferous vegetable intake and risk of breast cancer, though not all findings are consistent. Unfortunately, many of the population studies are limited by the imprecision of dietary assessment techniques, and the grouping of all diagnoses of breast cancer, regardless of stage, as a single outcome. It has been suggested that dietary compounds function as chemoprotection agents, by both blocking initiation and suppressing cell proliferation post- initiation and thus slowing disease progression. Sulforaphane (SFN), a phytochemical found in cruciferous vegetables has been demonstrated to inhibit breast cancer cell proliferation and enhance apoptosis, both in vitro and in vivo. More recently, the role of gene silencing via epigenetic alterations such as acetylation of histone structure has emerged an important factor in tumorigenesis and resistance to therapy in several cancers. Pharmacological inhibitors of histone deaceylases (HDAC) have induce apoptosis and decrease cancer cell proliferation in breast cancer cells both in vitro and in vivo. Based on the similarity of SFN and its metabolites to the conserved structure of HDAC inhibitors, we have gone on to demonstrate that dietary consumption of SFN limits tumor growth in animal models and decreases HDAC activity in human volunteers. We propose to conduct a randomized placebo-controlled trial to test the effectiveness of supplemental SFN intake in improving biomarkers for prognosis in DCIS patients and in altering HDAC activity. PUBLIC HEALTH RELEVANCE: The research proposed in this application is highly relevant because strategies that target epigenetic pathways have the potential to increase survival of DCIS patients, reduce health care costs associated with breast cancer, and improve the quality of life for thousands of American women. The successful completion of these smaller clinical studies will provide a strong scientific foundation for future large-scale human clinical intervention studies to combat breast cancer. These studies are also significant because of the potential to qualify or change recommendations for breast cancer patients and thereby increase their survival through simple dietary choices incorporating easily accessible and safe food products into a patient's diet.

描述（由申请人提供）： 萝卜硫素，一种饮食HDAC抑制剂，和预防DCIS进展项目摘要导管原位癌（DCIS）的诊断和医学管理的重大进展显着减少了疾病进展，提高了长期生存率。然而，有有限的医学上接受的新辅助治疗，以提高手术成功率的选择;虽然它是常见的女性寻求替代疗法，试图改善结果。因此，有必要对可能有效抑制DCIS进展的膳食物质进行科学指导的评估。组蛋白去乙酰化酶（HDAC）抑制剂作为新型化学保护剂最近产生了相当大的兴趣，因为它们靶向可在癌症发展的各个阶段发生的表观遗传事件。药理学HDAC抑制剂在体外和体内乳腺癌细胞中都具有抗癌作用。然而，这些药物的副作用使其不适合在患有浸润前疾病（DCIS）的女性中长期使用。萝卜硫素（SFN）是一种存在于十字花科蔬菜中的植物化学物质，近年来作为一种潜在的化学预防剂受到关注，但其确切的作用机制尚不清楚。基于饮食HDAC抑制剂在前列腺癌和结肠癌细胞中的研究，以及在健康志愿者中的研究，我们建议在乳腺癌模型中检查这些相关性，并测试补充SFN摄入在改善DCIS患者预后生物标志物和改变HDAC活性方面的有效性。这种预防癌症的饮食方法与传统的药理学HDAC抑制剂相比具有几个优点，包括毒性较小和易于给药。SFN作为化学预防方法的使用是重要的，因为其相对无毒的性质和多种生物学相关的抗肿瘤活性。公共卫生关系：导管原位癌（DCIS）的诊断和医疗管理的重大进展显着减少了疾病的进展，提高了长期生存率。然而，尽管总体结果良好，DCIS的有效治疗仍然需要手术和放射治疗，我们需要更好的方法来预防疾病进展。医学上可接受的新辅助治疗方案有限，可提高手术成功率，而针对浸润性疾病给予的典型新辅助化疗不会影响DCIS结局，部分原因是对导管间隙的渗透减少。因此，女性寻求替代疗法以改善结果是很常见的。因此，有必要对可能有效抑制DCIS进展的膳食物质进行科学指导的评估。一些流行病学研究报告了十字花科蔬菜摄入量与乳腺癌风险之间的负相关性，尽管并非所有研究结果都是一致的。不幸的是，许多人口研究受到饮食评估技术不精确的限制，以及将所有乳腺癌诊断分组，无论分期如何，作为单一结果。已经表明，膳食化合物通过阻断起始和抑制起始后的细胞增殖并因此减缓疾病进展而起到化学保护剂的作用。萝卜硫素（SFN）是一种在十字花科蔬菜中发现的植物化学物质，已被证明在体外和体内都能抑制乳腺癌细胞增殖并促进细胞凋亡。最近，通过表观遗传改变（如组蛋白结构的乙酰化）的基因沉默作用已成为几种癌症中肿瘤发生和治疗抗性的重要因素。组蛋白去乙酰化酶（HDAC）的药理学抑制剂在体内外均能诱导乳腺癌细胞凋亡并降低癌细胞增殖。基于SFN及其代谢物与HDAC抑制剂的保守结构的相似性，我们继续证明SFN的饮食消耗限制了动物模型中的肿瘤生长并降低了人类志愿者中的HDAC活性。我们建议进行一项随机安慰剂对照试验，以测试补充SFN摄入在改善DCIS患者预后生物标志物和改变HDAC活性方面的有效性。公共卫生相关性：本申请中提出的研究具有高度相关性，因为靶向表观遗传途径的策略有可能增加DCIS患者的生存率，降低与乳腺癌相关的医疗费用，并改善数千名美国女性的生活质量。这些小型临床研究的成功完成将为未来大规模人类临床干预研究提供强大的科学基础，以对抗乳腺癌。这些研究也是重要的，因为有可能资格或改变乳腺癌患者的建议，从而通过简单的饮食选择，将容易获得和安全的食品纳入患者的饮食中，提高他们的生存率。