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）： Sulforaphane是一种饮食中的HDAC抑制剂，预防DCIS进展项目总结了导管癌的诊断和医疗管理（DCIS）的重大进展（DCIS）显着降低了疾病进展并改善了长期生存。但是，新辅助疗法的医学接受选择有限，可以改善手术成功。尽管妇女通常寻求替代疗法以改善结果是很常见的。因此，需要科学地定向饮食物质评估，这些评估可能有效地抑制DCI的进展。组蛋白脱乙酰基酶（HDAC）的抑制剂已经引起了新的化学保护剂的近期兴趣，因为它们靶向可能发生在癌症发展的各个阶段的表观遗传事件。药理HDAC抑制剂在体外和体内都在乳腺癌细胞中具有抗癌作用。但是，这些药物的不利影响使得它们不适用于患有侵入性疾病（DCIS）女性的长期使用。 Sulforaphane（SFN）是十字花科蔬菜中发现的一种植物化学物质，最近作为一种潜在的化学预防剂而受到关注，但其精确的作用机理尚不清楚。基于前列腺和结肠癌细胞中饮食中HDAC抑制剂的研究，以及在健康志愿者中，我们建议在乳腺癌模型中检查这些关联，并测试补充SFN摄入量在改善DCIS患者中HDAC的预后和改变HDAC活性方面补充SFN摄入的有效性。这种预防癌症的饮食方法比常规药理HDAC抑制剂具有多个优点，包括毒性较小和易于给药。使用SFN作为化学预防方法非常重要，因为其相对无毒的性质和多种生物学相关的抗肿瘤活性。公共卫生相关性：导管癌（DCIS）的诊断和医疗管理的重大进展显着降低了疾病的进展并改善了长期生存。但是，尽管总体上取得了良好的结果，但对DCI的有效治疗仍然需要手术和放射治疗，我们需要更好的预防疾病进展的方法。新辅助治疗的医学接受选择有限，可以改善手术成功，而用于侵入性疾病的典型新辅助化学疗法并不影响导致导管空间的渗透率下降。因此，妇女通常寻求替代疗法以改善结果是很常见的。因此，需要科学地定向饮食物质评估，这些评估可能有效地抑制DCI的进展。许多流行病学研究报道了十字花科蔬菜摄入量与乳腺癌风险之间存在反比的关联，尽管并非所有发现都是一致的。不幸的是，许多人群研究受到饮食评估技术不精确的限制，并且无论阶段如何，所有乳腺癌的诊断都被视为一个单一的结果。已经提出，饮食化合物通过阻止起始和抑制细胞增殖后的开始，从而减缓疾病进展，从而充当化学保护剂。已证明在十字花科蔬菜中发现的一种植物化学物质硫烷（SFN）已被证明可以抑制乳腺癌细胞的增殖并增强体外和体内凋亡。最近，通过表观遗传学改变（例如组蛋白结构的乙酰化），基因沉默的作用已经出现了几种癌症的肿瘤发生和对治疗的耐药性的重要因素。组蛋白脱纤酶（HDAC）的药理抑制剂诱导凋亡并减少体外和体内乳腺癌细胞的癌细胞增殖。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的饮食消费限制了动物模型的肿瘤生长，并降低了人类志愿者的HDAC活性。我们建议进行一项随机的安慰剂对照试验，以测试补充SFN摄入量在改善DCIS患者预后和改变HDAC活性的生物标志物方面的有效性。公共卫生相关性：本应用程序中提出的研究非常相关，因为针对表观遗传途径的策略有可能提高DCIS患者的存活率，降低与乳腺癌相关的医疗保健成本，并提高成千上万美国妇女的生活质量。这些较小的临床研究的成功完成将为未来的大规模人类临床干预研究提供强大的科学基础，以打击乳腺癌。这些研究也很重要，因为有可能有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易于获得和安全的食品纳入患者的饮食中提高​​生存。