Mechanisms of prostate cancer prevention by Korean Angelica

韩国当归预防前列腺癌的机制

• 批准号: 9175121
• 负责人: JUNXUAN LU
• 金额: $ 13.09万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175121
• 关键词: Mechanisms; prostate; cancer; prevention; Korean

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.

描述（由申请人提供）：我们的长期目标是从韩国安吉里卡·吉斯·纳凯（Agn）（AGN）开发出无毒，低成本和有效的草药方式，以预防男性前列腺癌发生和转移。我们已经在临床前模型中显示了AGN乙醇提取物的明显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标的机械知识是向男性转化预防效益的重要障碍。当前应用的目的是在两个独立和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提取物在体内效应（a）主要通过吡喃氨基蛋白酶化合物及其代谢产物发挥作用。 （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介绍。我们计划通过追求三个具体目的来检验这些假设：目标1。通过将纯化化合物与AGN提取物和AGN提取物的功效和pyranocoumarin-nockout（KO）提取物进行比较，以抑制人类前列腺癌的生长和甲状腺神经毒素模型中的甲状腺毒素中的化学介质作用。 AIM 2。通过将其与AGN提取物和KO提取物进行比较，验证其在小鼠前列腺（Tramp）模型的转基因腺癌​​（Tramp）模型中对原发性致癌作用的介体作用。 AIM 3。通过聚焦分析和使用系统生物学方法的分子鉴定，确定体内疗效的关键细胞指数和分子生物标志物，包括血管生成，凋亡，细胞增殖和侵入性，并使用前两个目标中的合适组织来鉴定分子靶标。 预计目标1和2中提出的工作将批判性地评估吡喃糖蛋白和代谢产物作为化学介质对AGN提取物对前列腺原发性癌变和转移的抑制作用的化学介体的作用，并在小鼠模型中建立其长期安全谱。预计此类结果将对未来的重点研发工作和AGN草药产品的质量控制产生积极影响。 AIM 3结果有望鉴定体内分子靶标和细胞过程的候选者。在模型系统中，更好地了解活性化学物质及其分子靶标，可以进一步的机械研究和男性临床翻译的合理计划。此外，AGN提取物可能会导出功效和机制可导出到其他器官部位的癌症。在我们看来，提出的研究具有创新性，因为它与临床前癌症化学预防研究的现状相去甚远。使用过边缘药物化学方法（例如，基因敲除提取物）和系统生物学工具（例如ITRAQ蛋白质组学）的全面研究可以帮助将草药疗法转移到基于证据的互补和替代药物方面。