Nutrients and Prostate Cancer Prevention

营养素与前列腺癌预防

• 批准号: 7222714
• 负责人: YONG J LEE
• 金额: $ 7.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-13 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7222714
• 关键词: Adenocarcinoma; Affect; Allium; Allium Vegetable; Allium schoenoprasum; Apoptotic; Attenuated; Automobile Driving; Biochemical; Biological Assay; Body Size; Cancer Patient; Caspase; Categories; Cell Line; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Classification; Clinical; Complement component C1s; Consumption; Cysteine; Development; Disease; Early Diagnosis; Electron Transport; Enzymes; Epidemiologic Studies; Epithelial Cells; Evaluation; Food; Future; Garlic; Glutathione Reductase; Goals; Growth; Hormonal; Hydrolysis; Incidence; Ink; Intake; Leeks (dietary); Lesion; MAPK8 gene; MEKs; Malignant Neoplasms; Malignant neoplasm of prostate; Mastication; Measures; Metastatic Carcinoma; Mitochondria; Molecular Genetics; Mus; Normal Cell; Normal tissue morphology; Nutrient; Onions; Operative Surgical Procedures; Outcome Study; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Play; Preventive; Process; Production; Property; Prostate; Prostate Adenocarcinoma; Prostate-Specific Antigen; Quality of life; Radiation therapy; Reactive Oxygen Species; Recurrence; Research Design; Research Project Grants; Risk; Role; Signal Transduction Pathway; Staging; Sulfoxide; Sulfur Compounds; System; Testing; Therapeutic Agents; Thioredoxin; Transgenic Mice; Transgenic Organisms; Treatment Protocols; United States; alliin; base; cancer cell; cancer diagnosis; cancer risk; cancer type; clinical application; clinically significant; cytotoxic; day; diallyl trisulfide; genetic regulatory protein; glutaredoxin; glutathione peroxidase; improved; killings; men; pre-clinical; prostate cancer prevention

DESCRIPTION (provided by applicant): Background: Epidemiological studies continue to support the premise that increased consumption of allium vegetables, such as garlic, may be protective against the risk of certain types of cancers including prostate cancer. Recent studies have revealed that human prostate cancer cells as well as a cell line derived from prostate adenocarcinoma of a transgenic mouse (transgenic adenocarcinoma mouse prostate; TRAMP-C1 cell line) are highly sensitive to growth inhibition by diallyl trisulfide (DATS), a garlic-derived organosulfur compound (OSC). Interestingly, viability of a normal prostate epithelial cell line (PrEC, Clonetics) was minimally affected by DATS even at concentrations that were highly cytotoxic to the prostate cancer cells. These results are encouraging since selective killing of cancer cells is a highly desirable property of potential cancer preventive/therapeutic agents. Objective/Hypothesis: The underlying hypothesis driving this project is that DATS elevates the intracellular level of reactive oxygen species (ROS) and subsequently activates INK and caspases. The activation of the apoptotic pathway leads to the chemopreventive efficacy of DATS. Specific Aims: The specific aims of this project are to examine (1) whether DATS elevates the intracellular level of ROS by either increasing production of ROS through the mitochondrial electron transport chain or decreasing elimination of ROS through the glutathione peroxidase/glutathione reductase system, (2) whether redox-regulatory proteins such as thioredoxin (TRX) and glutaredoxin (GRX) recognize DATS-induced oxidative stress and activate the ASKl-MEK-JNK-Bim-Bax signal transduction pathway, and (3) whether intrinsic and extrinsic caspase pathways are involved in DATS- induced apoptotic death. Study design: In the proposed studies, the first aim will use a spectrofluorometer to measure the intracellular level of ROS. The second aim will be use of biochemical assays to investigate the ASK1-MEK-JNK signal transduction pathway. The third aim will use pharmacological and molecular genetic approaches to attenuate the activity/expression of caspase. Relevance: We believe that the successful outcome of this study will support the development and clinical application of DATS for the chemoprevention of human prostate cancer.

描述（由申请人提供）：背景：流行病学研究继续支持这样的前提，即增加葱蔬菜（例如大蒜）的消费可能具有保护某些类型的癌症（包括前列腺癌）的风险。最近的研究表明，人类前列腺癌细胞以及源自转基因小鼠的前列腺腺癌（转基因腺癌​​小鼠前列腺； Tramp-C1细胞系）的细胞系对二烯丙基三硫化物（DATS）的生长抑制高度敏感。有趣的是，即使在高度细胞毒性对前列腺癌细胞的浓度下，正常前列腺上皮细胞系（PREC，Clonetics）的生存力也受到DAT的影响。这些结果令人鼓舞，因为癌细胞的选择性杀死是潜在的癌症预防/治疗剂的高度理想的特性。客观/假设：驱动该项目的基本假设是DATS提高了活性氧（ROS）的细胞内水平，并随后激活墨水和胱天蛋白酶。凋亡途径的激活导致DAT的化学预防功效。具体目的：该项目的具体目的是检查（1）通过线粒体电子传输链增加ROS的产生，还是通过线粒体电子传输链增加ROS的细胞内ROS水平，或者通过谷胱甘肽过氧化物酶/谷胱甘肽复杂酶/谷胱甘肽还原酶系统（是否降低ROS）的消除，是识别型蛋白（2）theox-declox of theox-niperative of theox-niborative of theox- theox- theox- theox- theox- theox-niore（2） DATS诱导的氧化应激并激活Ask-Mek-JNK-BIM-BIM-BAX信号转导途径，（3）（3）固有和外在的caspase途径是否参与DATS诱导的凋亡死亡。研究设计：在拟议的研究中，第一个目标将使用谱荧光仪测量ROS的细胞内水平。第二个目的是使用生化测定来研究ASK1-MEK-JNK信号转导途径。第三个目标将使用药理和分子遗传学方法来减轻caspase的活性/表达。相关性：我们认为，这项研究的成功结果将支持DAT的开发和临床应用在人类前列腺癌的化学预防中。