Mechanisms of prostate cancer prevention by Korean Angelica

韩国当归预防前列腺癌的机制

基本信息

批准号：
8368398
负责人：
JUNXUAN LU
金额：
$ 43.49万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8368398
关键词：
Ablation Adenocarcinoma Adverse effects Affect American American Cancer Society Androgen Antagonists Androgen Receptor Androgens Angelica Angelica sinensis preparation Angiogenic Factor Animal Model Antibodies Antineoplastic Agents Apoptosis Asians Attention Biological Factors Biological Markers Biological Models Botanicals Cancer Model Cell Culture Techniques Cell Proliferation Cell physiology Cessation of life Chemicals Chemopreventive Agent Clinical Colon Carcinoma Complementary and alternative medicine Complex Cytotoxic agent Data Development Drug Kinetics Ethanol FDA approved Fibroblast Growth Factor 2 Fractionation Future Goals Growth Hormones Human Immunodeficient Mouse In Vitro Isomerism Knock-out Knowledge Koreans LNCaP Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediator of activation protein Methods Modality Modeling Molecular Molecular Target Mus Nature Neoplasm Metastasis Organ Outcome Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pre-Clinical Model Prevention Preventive Prostate Prostate carcinoma Proteomics Publishing Quality Control Quality of life Radiosurgery Recurrence Refractory Disease Research Research Personnel Rodent Role Safety Screening procedure Site Son Source Staging Stream Structure Systems Biology Targeted Research Testing Tissues Toxic effect Transgenic Organisms Translating Translations Tumor Angiogenesis War Work Xenograft Model alcohol effect angiogenesis base cancer cell cancer chemoprevention cancer diagnosis cancer prevention carcinogenesis cellular targeting chemotherapy comparative efficacy cost docetaxel drug discovery evidence base fighting in vivo indexing innovation insight male men mouse model novel pre-clinical prostate cancer prevention prostate carcinogenesis research and development statistics tool transcriptomics unpublished works

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to develop non-toxic, low-cost and efficacious herbal modalities from Korean Angelica gigas Nakai (AGN) for the prevention of prostate carcinogenesis and metastasis in men. We have shown in preclinical models significant prostate cancer growth-inhibitory and chemopreventive effects of AGN ethanol extracts without any observable toxicity to the host mice. Nevertheless, a lack of mechanistic knowledge of active chemicals and in vivo molecular targets is a significant roadblock to translating the preventive benefits to men. The objective for the current application is to generate mechanistic knowledge of (1) the active chemicals and (2) cellular and molecular targets in two independent and complementary prostate cancer models. We hypothesize that AGN extract exerts in vivo efficacy (a) mainly through pyranocoumarin compounds and their metabolite; (b) by affecting critical cellular processes and molecular targets, which can be effectively profiled through a systems-biology approach. We plan to test these hypotheses by pursuing three specific aims: Aim 1. Establish the chemical mediator role of the pyranocoumarins by comparing the efficacy of purified compounds with AGN extract and pyranocoumarin-knockout (KO) extract to inhibit human prostate cancer growth and metastasis in xenograft models in immunodeficient mice. Aim 2. Validate their mediator role for chemopreventive efficacy against primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model by comparing them with AGN extract and KO extract. Aim 3. Determine key cellular indices and molecular biomarkers of in vivo efficacy including angiogenesis, apoptosis, cell proliferation and invasiveness by focused analyses and identify molecular targets with systems-biology approaches, using suitable tissues from the first two aims. The work proposed in Aims 1 and 2 is expected to critically assess the role of pyranocoumarins and metabolites as chemical mediators for the inhibitory efficacy of AGN extract against prostate primary carcinogenesis and metastasis, and establish their long-term safety profiles in mice models. Such results are expected to positively impact future focused R&D efforts and quality control for AGN herbal products. Aim 3 results are expected to identify candidate in vivo molecular targets and cellular processes. Better knowledge of the active chemicals and their molecular targets in model systems enables further mechanistic studies and rational planning for clinical translation in men. Furthermore, the efficacy and mechanisms are likely exportable to the prevention of cancers of other organ sites by AGN extracts. The research proposed is innovative, in our opinion, because it represents a substantial departure from the status quo for preclinical cancer chemoprevention research of single-agent/single-target approach. The comprehensive research with cutting- edge medicinal chemistry methods (e.g., knockout extract) and systems-biology tools (e.g., iTRAQ proteomics) can help moving herbal remedies toward evidence-based complementary and alternative medicine. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is the most commonly diagnosed cancer in American men and is the second leading cause of male cancer death (American Cancer Society Statistics 2011). Treatment options for advanced PCa, including androgen-ablation therapy, radiation and surgery, do not offer a cure but delay the inevitable recurrence of the lethal advanced hormone-refractory disease. Chemotherapy using the cytotoxic drug docetaxel (the only FDA-approved chemo drug for PCa) for such advanced PCa offers only very limited survival benefit. All these treatments have significant side effects that negatively affect the quality of life of the patients and are costly. In contrast to treatments, cancer chemoprevention uses naturally-occurring or synthetic chemicals to block, reverse or delay carcinogenesis, progression and metastasis. However, due to the complex nature of carcinogenesis, main stream single-agent/single-target research has not led to the development of an effective chemopreventive modality for PCa so far. Oriental herbal extracts/natural products contain bioactive ingredients that can affect multiple targets crucial for cancer promotion and progression to exert chemopreventive efficacy. The proposed research will rigorously test the premise that the Korean angelica extracts can be safe and efficacious herbal supplements for PCa chemoprevention and will provide mechanistic insights into the active chemicals and their molecular targets to accelerate planning of clinical translation to help men fight PCa.

描述（由申请人提供）：我们的长期目标是开发无毒、低成本且有效的韩国当归（AGN）草药，用于预防男性前列腺癌的发生和转移。我们在临床前模型中证明了 AGN 乙醇提取物具有显着的前列腺癌生长抑制和化学预防作用，且对宿主小鼠没有任何可观察到的毒性。然而，缺乏对活性化学物质和体内分子靶点的机械知识是将预防益处转化为男性的重大障碍。当前应用的目标是在两个独立且互补的前列腺癌模型中生成（1）活性化学物质和（2）细胞和分子靶标的机械知识。我们假设 AGN 提取物发挥体内功效 (a) 主要通过吡喃香豆素化合物及其代谢物； (b) 通过影响关键的细胞过程和分子靶标，可以通过系统生物学方法有效地分析这些过程和分子靶标。我们计划通过实现三个具体目标来测试这些假设：目标 1. 通过比较纯化化合物与 AGN 提取物和吡喃香豆素敲除 (KO) 提取物抑制人类前列腺癌生长和转移的功效，确定吡喃香豆素的化学介导作用。免疫缺陷小鼠的异种移植模型。目标 2. 通过与 AGN 提取物和 KO 提取物进行比较，验证它们在转基因小鼠前列腺腺癌 (TRAMP) 模型中对原发性癌的化学预防功效的介导作用。目标 3. 通过集中分析确定体内功效的关键细胞指标和分子生物标志物，包括血管生成、细胞凋亡、细胞增殖和侵袭性，并使用前两个目标中的合适组织，通过系统生物学方法识别分子靶点。目标 1 和 2 中提出的工作预计将严格评估吡喃香豆素及其代谢物作为化学介质对 AGN 提取物对前列腺原发性癌变和转移的抑制功效的作用，并在小鼠模型中建立其长期安全性。这些结果预计将对 AGN 草药产品未来的重点研发工作和质量控制产生积极影响。目标 3 的结果预计将确定候选的体内分子靶标和细胞过程。更好地了解模型系统中的活性化学物质及其分子靶标，可以进行进一步的机制研究和合理规划男性临床转化。此外，其功效和机制可能可用于通过 AGN 提取物预防其他器官部位的癌症。我们认为，所提出的研究具有创新性，因为它与单药/单靶点方法的临床前癌症化学预防研究现状有很大不同。利用尖端药物化学方法（例如，敲除提取物）和系统生物学工具（例如，iTRAQ 蛋白质组学）进行的综合研究可以帮助将草药疗法转向基于证据的补充和替代医学。公共健康相关性：前列腺癌 (PCa) 是美国男性中最常诊断出的癌症，也是男性癌症死亡的第二大原因（美国癌症协会统计数据 2011）。晚期 PCa 的治疗选择，包括雄激素消融疗法、放射治疗和手术，不能治愈，但可以延缓不可避免的复发。致命的晚期激素难治性疾病。使用细胞毒性药物多西紫杉醇（FDA 批准的唯一治疗 PCa 的化疗药物）对此类晚期 PCa 进行化疗只能提供非常有限的生存获益。所有这些治疗都有显着的副作用，会对影响患者的生活质量，且费用昂贵。与治疗相反，癌症化学预防使用天然或合成的化学物质来阻止、逆转或延迟癌的发生、进展和转移。然而，由于致癌作用的复杂性，主流的单药/单靶点研究迄今为止尚未开发出有效的前列腺癌化学预防方式。东方草药提取物/天然产品含有生物活性成分，可以影响对癌症促进和进展至关重要的多个靶点，从而发挥化学预防功效。拟议的研究将严格测试韩国当归提取物可以作为前列腺癌化学预防的安全有效的草药补充剂的前提，并将提供对活性化学物质及其分子靶标的机制见解，以加速临床转化规划，帮助男性对抗前列腺癌。