Sulforaphane: A Dietary HDAC Inhibitor and Prevention of DCIS Progression

描述(由申请人提供)： 饮食中的HDAC抑制剂萝卜硫素和预防DCIS进展项目概述导管原位癌(DCIS)的诊断和医疗治疗方面的重大进步显著地减缓了疾病的进展，提高了长期存活率。然而，医学上接受的新辅助疗法以提高手术成功率的选择有限；尽管女性为了改善结果而寻求替代疗法是很常见的。因此，有必要对可能有效抑制DCIS进展的饮食物质进行科学的指导评估。组蛋白脱乙酰酶抑制剂(HDAC)作为一种新型的化学保护剂最近引起了相当大的兴趣，因为它们针对的是在癌症发展的不同阶段可能发生的表观遗传事件。药理作用的HDAC抑制剂在体内和体外对乳腺癌细胞均有抗癌作用。然而，这些药物的不良反应使它们不适合长期用于患有侵袭性前期疾病(DCIS)的妇女。萝卜硫素(SFN)是一种发现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药物而受到关注，但其确切的作用机制尚不清楚。基于饮食中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在改善DCIS患者预后的生物标志物和改变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物HDAC抑制剂相比有几个优点，包括毒性更低，更容易给药。SFN作为一种化学预防方法的使用意义重大，因为它相对无毒，具有多种生物学相关的抗肿瘤活性。公共卫生相关性：导管原位癌(DCIS)的诊断和医疗管理方面的重大进步显著地减缓了疾病的进展，提高了长期存活率。然而，尽管总体效果良好，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防止疾病的进展。为提高手术成功率，医学上可接受的新辅助治疗方法有限，对于侵袭性疾病给予的典型新辅助化疗不会影响DCIS的预后，部分原因是减少了对导管间隙的穿透。因此，女性为了改善结果而寻求替代疗法是很常见的。因此，有必要对可能有效抑制DCIS进展的饮食物质进行科学的指导评估。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关系，尽管并不是所有的发现都是一致的。不幸的是，许多人群研究受到饮食评估技术的不精确性的限制，以及将所有乳腺癌诊断分组，无论是什么阶段，作为一个单一的结果。有人认为，饮食化合物具有化学保护剂的作用，既可以阻止启动，也可以在启动后抑制细胞增殖，从而减缓疾病的进展。萝卜硫素(SFN)是十字花科蔬菜中发现的一种植物化学物质，在体外和体内都被证明能抑制乳腺癌细胞的增殖和促进细胞凋亡。最近，通过组蛋白结构乙酰化等表观遗传改变的基因沉默作用已经成为几种癌症发生和耐药的重要因素。组蛋白脱乙酰酶抑制剂(HDAC)在体内外均能诱导乳腺癌细胞的凋亡和抑制癌细胞的增殖。基于SFN及其代谢产物与HDAC抑制剂的保守结构的相似性，我们进一步证明了在动物模型中饮食摄入SFN限制了肿瘤的生长，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在改善DCIS患者预后的生物标志物和改变HDAC活性方面的有效性。

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.