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）：前列腺癌是美国的一个主要健康问题。迫切需要制定额外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，因为它们容易获得并且几乎没有毒性。特别是，冻干浆果制剂可以预防动物模型中的致癌作用，浆果中的鞣花酸和花青素可能是这种化学预防活性的原因，并且已经确定了这种作用的多种机制。在大鼠模型中，口服冻干浆果可减少乳腺癌的发生，这表明浆果的生物活性保护成分具有生物活性，并通过血流到达癌症部位。在食用冻干黑树莓的人类中，可以在尿液和血液中检测到鞣花酸和花青素，这表明人类也具有生物利用度。由于这些化合物具有抗氧化和/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，因此冻干黑树莓可以预防这种恶性肿瘤。然而，目前还没有研究测试冻干浆果抑制前列腺癌发生的能力。该项目将测试这样的假设：在相关大鼠模型中，膳食补充冻干黑树莓可抑制前列腺癌的发展，可能是通过生物活性浆果成分的抗氧化和/或抗炎活性以及其他抗癌机制活性的混合物。事实上，所有关于黑树莓在其他动物模型中抗癌作用的临床前数据都是在大鼠身上开发的。因此，我们将在原理验证实验中使用两种成熟且特征明确的前列腺癌大鼠模型来检验这一假设，其中一种已针对化学预防研究进行了验证，另一种则仅涉及炎症成分。重要的是，这种双模型方法应该能够捕获黑树莓的多种抗癌机制。具体目标是：(1) 确定在 Wistar WU 大鼠的 MNU 加睾酮模型中，饲喂冻干黑树莓是否会降低前列腺癌的发病率或多重性和/或减少肿瘤生长，该模型不涉及炎症，不太可能涉及氧化压力大，但很容易进展为转移性癌症； (2) 确定在 Noble (NBL) 大鼠雌二醇加睾酮模型中饲喂冻干黑树莓是否会降低前列腺癌的发病率或多重性，和/或降低炎症和发育异常病变的程度，NBL 是一种独特地涉及氧化应激和炎症的模型，但不易进展为转移性癌症。我们还将从目标 1 和 2 的研究中保存组织，用于探索喂养黑树莓对氧化应激、细胞增殖和细胞凋亡标记物的影响，以及测量前列腺组织中的鞣花酸和花青素。所提出的具体目标的积极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。 公共卫生相关性：前列腺癌是美国的一个主要健康问题。迫切需要制定额外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，因为它们容易获得并且几乎没有毒性。冻干浆果制剂可以预防动物模型中的致癌作用，并且已经确定了这种作用的多种机制。浆果的生物活性保护成分被肠道吸收，可以通过血流到达癌症部位，在食用冻干黑树莓的人类中，尿液和血液中可以检测到浆果特异性化合物，表明它们被肠道吸收。然而，还没有研究测试冻干浆果抑制前列腺癌发展的能力。该项目将测试以下假设：在相关大鼠模型中，膳食补充剂中含有冻干黑树莓可抑制前列腺癌的发展。我们建议在两种成熟且特征明确的前列腺癌动物模型的实验中检验这一假设，其中一种会发展为进行性恶性癌症并已用于化学预防研究，另一种则仅涉及炎症。该项目的具体目标是：（1）确定在不涉及炎症但容易进展为转移性癌症的大鼠模型中，饲喂冻干黑树莓是否可以减少前列腺癌。 (2) 确定在涉及炎症但不易进展为转移性癌症的大鼠模型中，饲喂冻干黑树莓是否可以减少前列腺癌。所提出的具体目标的积极结果将为前列腺癌患者的进一步机制和临床试验提供依据。