Effect of Rhamnetin on Oxidative Stress and Prostate Cancer

描述(申请人提供)：这项研究的主要目标是确定鼠李素，一种天然植物黄醇，通过Klotho(KL)和Fox‘O’信号转导在TraMP小鼠中保持对氧化应激的抵抗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，细胞和组织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的丢失有关。因此，迫切需要一种能够在细胞水平上降低氧化应激的有效药物。Rhamnetin是一种很有前途的药物，在ORAC(氧自由基吸收能力)量表中排名很高，可能是减少氧化应激和传递癌症化学预防作用的重要新范式。这项拟议的研究将探索鼠李素在细胞水平上减少氧化应激的潜力，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素是否有潜力调节非转基因动物和TRAMP模型中随年龄增长的KL和Foxo3a水平，保持对氧化应激的抵抗力，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，并了解氧化应激产生的基本机制在调节前列腺癌的发展中随年龄的增长而增加。公共卫生意义：迫切需要有效的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，而不产生任何副作用。因此，使用丁香和其他草药制剂中的一种新型试剂，鼠李素将被试验用于预防前列腺癌和延长无病生存期。前列腺癌是美国男性人口老龄化的疾病，也是仅次于肺癌的第二大杀手，因此迫切需要预防策略。

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.