Preventive Activity of Black Raspberries against Prostate Cancer

黑树莓对前列腺癌的预防活性

• 批准号: 7963473
• 负责人: MAARTEN C BOSLAND
• 金额: $ 20.49万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7963473
• 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。迫切需要制定其他新策略来防止这种恶性肿瘤的发展。食品用于预防癌症是有吸引力的，因为它们很容易获得，几乎没有毒性。尤其是冻干的浆果制剂可以预防动物模型中的致癌作用，浆果中发生的椭圆酸和花青素可能是对这种化学预防活性的原因，并且已经确定了多种机制。口服冻干浆果在大鼠模型中降低了乳腺癌的作用，表明浆果的生物活性保护成分是生物利用的，并通过血流到达癌症。在消耗冻干黑覆盆子的人类中，在尿液和血液中也可以检测到椭圆酸和花色苷，表明人类的生物利用度。由于这些化合物具有抗氧化剂和/或抗炎活性，并且炎症过程和氧化应激与人类前列腺癌的病因有关，因此冻干的黑色覆盆子可能会预防这种恶性肿瘤。但是，没有研究测试冻干浆果抑制前列腺癌发生的能力。该项目将检验以下假设：在相关的大鼠模型中，用冻干的黑色覆盆子补充饮食会抑制前列腺癌的发展，这可能是通过抗氧化剂和/或抗炎性活性和其他抗癌机制的混合物的生物活性浆果成分活性。几乎所有关于黑覆盆子在其他动物模型中的抗癌作用的临床前数据均已在大鼠中开发出来。因此，我们将使用两个公认的良好特征的前列腺癌发生大鼠模型在原则实验中检验这一假设，该模型已经过化学预防研究验证，一个唯一涉及炎症成分。这种双重模型方法应重要地允许捕获黑色覆盆子的多种抗癌机制。具体目的是：（1）确定喂养冻干的黑色覆盆子会降低前列腺癌的发生或多样化和/或减少MNU中的肿瘤生长，而Wistar Wu大鼠中的MNU加睾丸激素模型是否会涉及炎症，该模型不涉及炎症，并且不太可能涉及氧化压力，但可以随时进行氧化性毒性进展，从而伴随着转化的转化性癌症； （2）确定喂养冻干的黑色覆盆子是否会降低前列腺癌的发病率或多样性，并且/或降低雌二醇加上睾丸激素模型（NBL）大鼠的炎症和发育不良病变的程度，这种模型是一种独特的氧化应激和炎症和炎症的模型，但既不含有氧化的毒性和炎症，又不可预测的癌症。我们还将从目标1和2的研究中节省组织，以探索喂养黑色覆盆子对氧化应激，细胞增殖和凋亡标记的影响，以及对前列腺组织中椭圆酸和花青素的测量。提出的特定目标的积极结果将为进一步的机械研究和前列腺癌患者的临床试验提供理由。 公共卫生相关性：前列腺癌是美国的主要健康问题。迫切需要制定其他新策略来防止这种恶性肿瘤的发展。食品用于预防癌症是有吸引力的，因为它们很容易获得，几乎没有毒性。冷冻浆果制剂可以防止动物模型中的致癌作用，并且已经确定了多种机制。浆果的生物活性保护成分在肠道中被吸收，可以通过血流和消耗冻干黑色覆盆子的人类到达癌症部位，尿液中可检测到浆果特异性化合物，并表明它们在肠道中被吸收。但是，没有研究测试冻干浆果抑制前列腺癌发展的能力。该项目将检验以下假设：用冻干的黑色覆盆子补充饮食会抑制相关大鼠模型中前列腺癌的发展。我们建议在实验中检验这一假设，该假设具有前列腺癌发生的两种良好且特征良好的动物模型，该模型逐渐发展出恶性癌，并且已用于化学预防研究，一种尤其涉及炎症。该项目的具体目的是：（1）确定在不涉及炎症但很容易发展为转移性癌症的大鼠中，在大鼠的模型中，喂养冻干的黑色覆盆子是否会减少前列腺癌。 （2）确定在涉及炎症但不容易发展为转移性癌症的大鼠模型中，喂养冻干的黑色覆盆子是否会减少前列腺癌。提出的特定目标的积极结果将为前列腺癌患者的进一步机械和临床试验提供基本原理。