Preventive Activity of Black Raspberries against Prostate Cancer

黑树莓对前列腺癌的预防活性

• 批准号: 8101295
• 负责人: MAARTEN C BOSLAND
• 金额: $ 16.56万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101295
• 关键词: 2-Acetylaminofluorene; A/J Mouse; Address; Aflatoxins; Animal Disease Models; Animal Model; Animals; Anthocyanins; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Area; Berry; Bioavailable; Biological Availability; Blood; Breast; Cancer Model; Cancer Patient; Carcinogens; Cell Culture Techniques; Cell Proliferation; Cells; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical Trials; Complementary and alternative medicine; Consumption; Data; Development; Dietary Supplementation; Diethylnitrosamine; Disseminated Malignant Neoplasm; Dutasteride; Ellagic Acid; Epidemiologic Studies; Esophagus; Estradiol; Estrogens; Etiology; Exhibits; Exploratory/Developmental Grant; Finasteride; Food; Freeze Drying; Fruit; Future; Gastrointestinal Neoplasms; Gastrointestinal tract structure; Health; Human; Inbred ACI Rats; Incidence; Inflammation; Inflammatory; Lesion; Liver neoplasms; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of prostate; Mammary Tumorigenesis; Measurement; Mediating; Methylnitrosourea; Modeling; NIH Program Announcements; Oral; Oral Administration; Organ; Outcome; Oxidative Stress; Oxidoreductase; Patients; Powder dose form; Preparation; Preventive; Process; Property; Prostate; Raspberries; Rattus; Research; Selenomethionine; Signal Transduction Pathway; Site; Source; Staging; Stream; Testing; Testosterone; Tissues; Tocopherols; Toxic effect; United States; Urine; anticancer activity; anticancer research; cancer chemoprevention; cancer prevention; cancer risk; cancer site; carcinogenesis; feeding; fruits and vegetables; inhibitor/antagonist; innovation; novel strategies; pre-clinical; pre-clinical research; premature; prevent; prostate carcinogenesis; protective effect; public health relevance; research study; response; tumor; tumor growth; urinary

DESCRIPTION (provided by applicant): Prostate cancer is a major health problem in the United States. There is an urgent need to develop additional, new strategies to prevent the development of this malignancy. The use of food products for cancer prevention is appealing because they are readily available and exhibit little to no toxicity. In particular lyophilized berry preparations can prevent carcinogenesis in animal models, ellagic acid and anthocyanins occurring in berries may be responsible of for this chemopreventive activity, and multiple mechanisms of this effect have been identified. Oral administration of lyophilized berries reduced mammary carcinogenesis in a rat model, indicating that bioactive protective constituents of berries are bioavailable and reach cancer sites via the blood stream. In humans consuming lyophilized black raspberries, ellagic acid and anthocyanins are detectable in urine and blood indicating bioavailability in humans as well. Because these compounds have anti-oxidant and/or anti-inflammatory activity and inflammatory processes and oxidative stress are involved in the etiology of human prostate cancer, lyophilized black raspberries may protect against this malignancy. However, there have been no studies testing the ability of lyophilized berries to inhibit prostate carcinogenesis. This project will test the hypothesis that dietary supplementation with lyophilized black raspberries inhibits the development of prostate cancer in relevant rat models, possibly through a mixture of anti-oxidant and/or anti- inflammatory activity and other anti-cancer mechanisms activity of bioactive berry constituents. Virtually all preclinical data on anticancer effects of black raspberries in other animal models have been developed in rats. Therefore, we will test this hypothesis in proof-of-principle experiments using two well-established and well- characterized rat models of prostate carcinogenesis, one that has been validated for chemoprevention studies and one that uniquely involves an inflammatory component. This dual model approach should importantly allow capturing multiple anticancer mechanisms of black raspberries. The Specific Aims are: (1) Determine whether feeding lyophilized black raspberries reduces prostate cancer incidence or multiplicity and/or reduces tumor growth in the MNU plus testosterone model in Wistar WU rats, a model that does not involve inflammation and is unlikely to involve oxidative stress, but readily progresses to metastatic cancer; and (2) determine whether feeding lyophilized black raspberries reduces prostate cancer incidence or multiplicity, and/or reduces the extent of inflammation and dysplastic lesions in the estradiol plus testosterone model in Noble (NBL) rats, a model that uniquely involves oxidative stress and inflammation, but does not readily progresses to metastatic cancer. We will also save tissues from the studies of Aims 1 and 2 for exploration of effects of feeding black raspberries on markers of oxidative stress, cell proliferation, and apoptosis, as well as measurement of ellagic acid and anthocyanins in prostate tissue. Positive results from the proposed specific aims would provide rationale for further mechanistic studies and clinical trials with prostate cancer patients. PUBLIC HEALTH RELEVANCE: Prostate cancer is a major health problem in the United States. There is an urgent need to develop additional, new strategies to prevent the development of this malignancy. The use of food products for cancer prevention is appealing because they are readily available and exhibit little to no toxicity. Freeze- dried berry preparations can prevent carcinogenesis in animal models and multiple mechanisms of this effect have been identified. Bioactive protective components of berries are taken up in the gut and can reach cancer sites via the blood stream and in humans consuming lyophilized black raspberries, berry-specific compounds are detectable in urine and blood indicating that they are taken up in the gut. However, there have been no studies testing the ability of lyophilized berries to inhibit prostate cancer development. This project will test the hypothesis that dietary supplementation with lyophilized black raspberries inhibit the development of prostate cancer in relevant rat models. We propose to test this hypothesis in experiments with two well-established and well-characterized animal models of prostate carcinogenesis, one that develop progressively malignant cancer and that has been used for chemoprevention studies, and one that uniquely involves inflammation. The specific aims of the project are: (1) Determine whether feeding lyophilized black raspberries reduces prostate cancer in a model in rats that does not involve inflammation, but readily progresses to metastatic cancer. (2) Determine whether feeding lyophilized black raspberries reduces prostate cancer in a rat model that involves inflammation, but does not readily progresses to metastatic cancer. Positive results from the proposed specific aims would provide rationale for further mechanistic and clinical trials with prostate cancer patients.

描述（由申请人提供）：前列腺癌是美国的主要健康问题。我们迫切需要制定更多的新策略来预防这种恶性肿瘤的发展。使用食品来预防癌症很有吸引力，因为它们很容易获得，而且几乎没有毒性。特别是冻干浆果制剂可以在动物模型中预防癌变，浆果中发生的鞣花酸和花青素可能负责这种化学预防活性，并且这种作用的多种机制已经确定。在大鼠模型中口服冻干浆果减少了乳腺癌的发生，表明浆果的生物活性保护成分是生物可利用的，并通过血液到达癌症部位。在食用冻干黑覆盆子的人类中，尿液和血液中可检测到鞣花酸和花青素，这也表明它们在人类中的生物利用度。由于这些化合物具有抗氧化和/或抗炎活性，炎症过程和氧化应激与人类前列腺癌的病因有关，冻干黑覆盆子可以预防这种恶性肿瘤。然而，还没有研究测试冻干浆果抑制前列腺癌的能力。本项目将在相关大鼠模型中验证膳食补充冻干黑树莓抑制前列腺癌发展的假设，可能是通过抗氧化和/或抗炎活性以及生物活性浆果成分的其他抗癌机制活性的混合物。事实上，所有在其他动物模型中关于黑树莓抗癌作用的临床前数据都是在大鼠身上得到的。因此，我们将在原理验证实验中测试这一假设，使用两种已经建立并具有良好特征的前列腺癌大鼠模型，一种已经在化学预防研究中得到验证，另一种只涉及炎症成分。这种双重模型方法应该重要地允许捕获黑树莓的多种抗癌机制。具体目的是：(1)确定在Wistar WU大鼠的MNU +睾酮模型中，喂养冻干黑树莓是否能降低前列腺癌的发病率或多样性和/或降低肿瘤生长，该模型不涉及炎症，不太可能涉及氧化应激，但很容易发展为转移性癌症；(2)确定在雌二醇加睾酮模型的Noble （NBL）大鼠中，喂养冻干黑树莓是否能降低前列腺癌的发病率或多样性，和/或降低炎症和发育不良病变的程度，该模型独特地涉及氧化应激和炎症，但不易进展为转移性癌症。我们还将保留Aims 1和2研究中的组织，用于探索喂食黑覆盆子对氧化应激、细胞增殖和凋亡标志物的影响，以及前列腺组织中鞣花酸和花青素的测量。提出的具体目标的阳性结果将为进一步的机制研究和前列腺癌患者的临床试验提供依据。