Effect of Rhamnetin on Oxidative Stress and Prostate Cancer

鼠李素对氧化应激和前列腺癌的影响

• 批准号: 8399168
• 负责人: Sanjeev Shukla
• 金额: $ 7.85万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-03 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399168
• 关键词: Adenocarcinoma; Adverse effects; Age; Aging; Aging-Related Process; American Association of Cancer Research; Antioxidants; Apoptosis; Atherosclerosis; Biological Assay; Blood; Blood Circulation; Cancer Patient; Cell Culture Techniques; Cell Nucleus; Cells; Chemopreventive Agent; Clove; Cytoplasm; Cytosol; Data; Data Sources; Development; Diet; Disease; Disease-Free Survival; Down-Regulation; Drug Metabolic Detoxication; Epithelial Cells; Event; Exhibits; Fibroblast Growth Factor Receptors; Flavanol; Flavonoids; Food; Foxes; Generations; Genes; Goals; Growth; Human; IRS1 gene; Immunoprecipitation; Impaired cognition; In Vitro; Individual; Infertility; Insulin; Insulin-Like Growth Factor I; Integral Membrane Protein; Lateral; Lead; MAP Kinase Gene; MAPK14 gene; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Masks; Modeling; Molecular Chaperones; Molecular Target; Mus; Normal Cell; Nuclear; Oral; Osteoporosis; Oxidative Stress; Paraquat; Pathogenesis; Phosphorylation; Phosphotransferases; Plant Preparations; Plants; Plasma; Play; Population; Predisposition; Premature aging syndrome; Prevention strategy; Prostate; Prostate carcinoma; Prostatic Diseases; Proteins; Public Health; Reactive Oxygen Species; Regulation; Reporting; Resistance; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Stream; Stress; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Suppression; Tumor Suppressor Genes; United States; Work; age effect; age related; base; cancer cell; cancer initiation; cell growth; clinically relevant; dietary supplements; feeding; forkhead protein; high risk; human FRAP1 protein; human disease; in vivo; klotho protein; male; meetings; mouse model; neoplastic cell; normal aging; novel; oncoprotein p21; p66(ShcA) protein; prevent; prostate cancer prevention; protective effect; protein expression; red wine; response; transcription factor

DESCRIPTION (provided by applicant): The major goal of this study is to determine the potential of rhamnetin, a natural plant flavanol, in maintaining resistance against oxidative stres and prevention of prostate cancer through klotho (KL) and Fox 'O' signaling in TRAMP mice. Aging is a major risk factor for prostate cancer and it has been proposed that the mechanisms of aging and prostate cancer are intimately related with each other. With increasing age, there is an increase in oxidative stress at cellular and organismal level, which correlates with reduced serum levels of secreted KL protein and loss of FOXO3a from the nucleus. Hence, there is an urgent need for an effective agent, which can reduce oxidative stress at cellular level. Rhamnetin, is a promising agent, ranks high in ORAC (Oxygen Radical Absorbance Capacity) scale may be an important new paradigm for reducing oxidative stress and impart cancer chemopreventive effects. The proposed study will explore the potential of rhamnetin in reducing oxidative stress at cellular level and compensate the loss of KL and FOXO3a in cell culture studies. Furthermore, in vivo studies will determine whether rhamnetin has potential to regulate KL and Foxo3a levels in the non-transgenic as well as in TRAMP model with increasing age, maintaining resistance against oxidative stress which could lead to inhibition of prostate cancer and disease free survival. Our long term goal is to develop a novel and effective preventive strategy for prostate cancer and to understand the basic mechanism of oxidative stress generation with increasing age in the regulation of prostate cancer development. Public Health Significance: There is an immediate need for the effective and clinically relevant strategies for inhibition of prostate cancer growth, mainly in high-risk individuals, without any side effects. Hereby using a novel agent from the clove and other herbal preparation, rhamnetin will be tested to prevent prostate cancer and prolong disease free survival. Since prostate cancer is a disease of aging male population and second largest killer after lung cancer in the United States, prevention strategies are urgently needed. PUBLIC HEALTH RELEVANCE: The proposed study will investigate the potential role of a natural compound, rhamnetin, in a diet- based strategy to maintain resistance against oxidative stress in the prevention of prostate cancer in a relevant Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Klotho and Fox 'O' transcription factors are critical molecular targets involved in oxidative stress and aging, where the effects of rhamnetin has not been elucidated. Results obtained from these studies will provide supportive data and evidence to further test rhamnetin as a means to protect against prostate cancer.

描述（由申请人提供）：本研究的主要目的是确定鼠李糖素（一种天然植物黄烷醇）通过klotho （KL）和Fox ‘O’信号传导在TRAMP小鼠中维持抗氧化应激和预防前列腺癌的潜力。衰老是前列腺癌的主要危险因素，已有研究认为衰老与前列腺癌的发病机制密切相关。随着年龄的增长，细胞和机体水平的氧化应激增加，这与血清分泌的KL蛋白水平降低和细胞核中FOXO3a的缺失有关。因此，迫切需要一种能在细胞水平上降低氧化应激的有效药物。鼠李素是一种很有前途的药物，在ORAC（氧自由基吸收能力）水平上排名很高，可能是一种重要的新范式，用于减少氧化应激和赋予癌症化学预防作用。本研究将探索鼠李糖素在细胞水平上降低氧化应激的潜力，并在细胞培养研究中弥补KL和FOXO3a的损失。此外，体内研究将确定鼠李糖素是否有可能随着年龄的增长调节非转基因和TRAMP模型中的KL和Foxo3a水平，维持对氧化应激的抵抗，从而抑制前列腺癌和无病生存。我们的长期目标是开发一种新的有效的前列腺癌预防策略，并了解氧化应激随年龄增长在前列腺癌发展中的调节作用的基本机制。公共卫生意义：迫切需要有效和临床相关的策略来抑制前列腺癌的生长，主要是在高危人群中，没有任何副作用。在此，我们将使用一种从丁香和其他草药制剂中提取的新型药剂，来测试鼠李糖素对预防前列腺癌和延长无病生存期的作用。由于前列腺癌是美国男性老龄化人群的疾病，是仅次于肺癌的第二大杀手，因此迫切需要预防策略。