Mechanisms of prostate cancer prevention by Korean Angelica

韩国当归预防前列腺癌的机制

• 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
• 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prostate cancer prevention; prostate carcinogenesis; research and development; statistics; tool; transcriptomics; unpublished works

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）：我们的长期目标是从韩国当归（AGN）中开发无毒、低成本和有效的草药形式，用于预防男性前列腺癌的发生和转移。我们已经在临床前模型中显示了AGN乙醇提取物的显著前列腺癌生长抑制和化学预防作用，而对宿主小鼠没有任何可观察到的毒性。然而，缺乏活性化学物质和体内分子靶点的机制知识是将预防益处转化为男性的重大障碍。本申请的目的是在两个独立和互补的前列腺癌模型中产生（1）活性化学物质和（2）细胞和分子靶标的机制知识。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产物;（B）通过影响关键细胞过程和分子靶点，这可以通过系统生物学方法有效地分析。我们计划通过追求三个具体目标来测试这些假设：目标1。通过比较纯化的化合物与AGN提取物和吡喃香豆素敲除（KO）提取物在免疫缺陷小鼠的异种移植模型中抑制人前列腺癌生长和转移的功效，确定吡喃香豆素的化学介质作用。目标二。通过与AGN提取物和KO提取物的比较，证实它们在小鼠前列腺转基因腺癌（TRAMP）模型中对原发癌发生的化学预防功效的介导作用。目标3。通过重点分析确定体内疗效的关键细胞指标和分子生物标志物，包括血管生成、凋亡、细胞增殖和侵袭性，并使用前两个目标的合适组织，采用系统生物学方法确定分子靶点。 目标1和2中提出的工作预计将严格评估吡喃香豆素和代谢物作为化学介质对AGN提取物抑制前列腺原发性癌发生和转移的作用，并在小鼠模型中建立其长期安全性特征。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。目的3的结果有望确定候选的体内分子靶点和细胞过程。更好地了解模型系统中的活性化学物质及其分子靶点，可以进一步进行机制研究和合理规划男性临床转化。此外，AGN提取物的功效和机制可能可用于预防其他器官部位的癌症。在我们看来，所提出的研究是创新的，因为它代表了对单药/单靶点方法的临床前癌症化学预防研究现状的实质性偏离。采用尖端药物化学方法进行的综合研究（例如，敲除提取物）和系统生物学工具（例如，iTRAQ蛋白质组学）可以帮助将草药疗法转向基于证据的补充和替代医学。 公共卫生相关性：前列腺癌（PCa）是美国男性中最常诊断的癌症，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，包括雄激素消融治疗，放射治疗和手术，不能治愈，但可以延迟不可避免的复发。 致命的晚期难治性疾病使用细胞毒性药物多西他赛（唯一FDA批准的PCa化疗药物）对此类晚期PCa进行化疗仅提供非常有限的生存益处。所有这些治疗都有明显的副作用， 患者的生活质量和成本都很高。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断、逆转或延迟癌症发生、进展和转移。然而，由于癌发生的复杂性，主流的单剂/单靶点研究至今尚未导致有效的PCa化学预防模式的发展。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，以发挥化学预防功效。拟议的研究将严格测试韩国当归提取物可以作为PCa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点的机制见解，以加速临床转化的规划，以帮助男性对抗PCa。