Identification of Natural Compound Combinations for Prevention of Prostate Cancer

预防前列腺癌的天然化合物组合的鉴定

基本信息

批准号：
10320338
负责人：
John DiGiovanni
金额：
$ 49.19万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320338
关键词：
Allografting American Cancer Society Biological Assay Biological Availability CXCL12 gene CXCR4 gene Cancer Cell Growth Cancer Etiology Cause of Death Cell Survival Cells Cessation of life Chemoprevention Chemopreventive Agent Curcumin DU145 Data Development Diagnosis Diet Epithelial Cells Evaluation FRAP1 gene Future Glutamine Glycyrrhetinic Acid Goals Growth Human Impairment In Vitro Lead Libraries Lipids Malignant Neoplasms Malignant neoplasm of prostate Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Mus Oncogenic Pathway interactions Phytochemical Population Prevention Property Prostate Research Resveratrol Serum Signal Pathway Testing Tissues Transgenic Mice Treatment outcome United States absorption base cancer chemoprevention cancer diagnosis cancer stem cell cell growth cell motility clinically relevant dietary experimental study in vivo men metabolomics mortality mouse model neoplastic cell novel novel strategies prostate cancer cell prostate cancer cell line prostate cancer model prostate cancer prevention prostate cancer risk screening silibinin stable isotope tumor tumor growth uptake ursolic acid

项目摘要

PROJECT SUMMARY The overall goal of the proposed research is to develop novel strategies, using combinations of phytochemicals for the prevention of prostate cancer (PCa). In the United States, PCa is the most frequently diagnosed non- cutaneous cancer and the second leading cause of cancer-related mortality in men with an estimated 164,690 new cases and an estimated 29,430 deaths in 2018 (American Cancer Society). We have recently found that several combinations of natural compounds together with ursolic acid (UA) [i.e., UA + curcumin (CURC) and UA + resveratrol (RES)] are highly effective at depleting cellular ATP levels and at inhibiting the growth/survival of both mouse (HMVP2, a PCa cell line derived from HiMyc mice) and human (DU145, C4-2B) PCa cell lines. Both of these combinations produced a synergistic inhibition of PCa cell growth in vitro and also synergistically inhibited the growth of HMVP2 cells in an allograft tumor model when administered in the diet. Furthermore, metabolomics analyses of PCa tumor cells indicate that the effective phytochemical combinations reduced glutamine uptake which likely contributed to the enhanced tumor growth inhibitory activity observed. We have recently obtained additional synergistic combinations using a two-tiered screen with enoxolone (ENO) as the lead compound involving ATP depletion and inhibition of glutamine uptake. One of these combinations (ENO + silibinin) was further tested and shown to synergistically inhibit growth of HMVP2 PCa cells in vivo as further proof of principle for this approach. In this proposal, we will test the hypothesis that combinations of certain natural compounds that can be identified by their ability to deplete cellular ATP and block glutamine uptake will be highly effective, synergistic chemopreventive agents for PCa. We will also test the hypothesis that effective combinations will have the ability to inhibit specific oncogenic metabolism and signaling pathways important for PCa development and progression. The Specific Aims are: 1: Evaluate combinations of natural compounds for their ability to synergistically and selectively inhibit growth properties of PCa cell lines; 2: Examine the most effective combinations of agents identified in Specific Aim 1 for their effects on oncogenic signaling pathways (e.g., Stat3, Src, NFκB, AMPK, mTOR and CXCL12/CXCR4) as well as metabolic pathway changes (e.g., glutamine uptake and utilization, lipid profiles, etc); 3: Examine the effects of selected natural compound combinations for their ability to prevent PCa development/progression in two relevant mouse models of PCa (HiMyc and PTENpcko); and 4: Continue screening larger libraries of natural compounds to identify novel top-hit compounds and screen compound combinations for their ability to synergistically deplete cellular ATP levels and block glutamine uptake in PCa cell lines. Completion of the proposed studies will lead to novel approaches for identifying combinations of phytochemicals for cancer chemoprevention studies and could lead to the identification of one or more novel and clinically relevant phytochemical combinations for prevention of PCa.

项目概要拟议研究的总体目标是利用植物化学物质的组合来开发新策略用于预防前列腺癌 (PCa) 在美国，PCa 是最常诊断的非癌症。皮肤癌是导致男性癌症相关死亡的第二大原因，估计有 164,690 人死亡我们最近发现，2018 年新增病例和估计死亡人数为 29,430 人。天然化合物与熊果酸 (UA) 的几种组合[即 UA + 姜黄素 (CURC) 和 UA + 白藜芦醇 (RES)] 在消耗细胞 ATP 水平和抑制生长/存活方面非常有效小鼠（HMVP2，一种源自 HiMyc 小鼠的 PCa 细胞系）和人类（DU145，C4-2B）PCa 细胞系。这两种组合在体外对 PCa 细胞生长产生协同抑制作用，并且也具有协同作用当在饮食中施用时，抑制同种异体移植肿瘤模型中 HMVP2 细胞的生长。 PCa 肿瘤细胞的代谢组学分析表明，有效的植物化学组合减少了我们观察到，谷氨酰胺的摄取可能有助于增强肿瘤生长抑制活性。最近使用以enoxolone（ENO）为基础的两层筛选获得了额外的协同组合涉及 ATP 消耗和谷氨酰胺摄取抑制的先导化合物（ENO +）之一。水飞蓟宾）经过进一步测试并显示其在体内协同抑制 HMVP2 PCa 细胞的生长，进一步证明在本提案中，我们将测试以下组合的假设。某些天然化合物可以通过其消耗细胞 ATP 和阻断的能力来识别谷氨酰胺摄取将是前列腺癌的高效、协同化学预防剂。有效组合能够抑制特定致癌物质的假设对 PCa 发生和进展很重要的代谢和信号通路。是： 1：评估天然化合物组合的协同和选择性抑制能力 PCa 细胞系的生长特性；2：检查特定药物中确定的最有效的药物组合目标 1：它们对致癌信号通路（例如 Stat3、Src、NFκB、AMPK、mTOR 和 CXCL12/CXCR4）以及代谢途径的变化（例如谷氨酰胺的摄取和利用、血脂谱、等）；3：检查所选天然化合物组合预防 PCa 的能力两种相关 PCa 小鼠模型（HiMyc 和 PTENpcko）的发育/进展；以及 4：继续筛选更大的天然化合物库，以识别新的热门化合物并筛选化合物组合能够协同消耗细胞 ATP 水平并阻止 PCa 中谷氨酰胺的摄取完成拟议的研究将带来识别细胞系组合的新方法。植物化学物质用于癌症化学预防研究，并可能导致鉴定一种或多种新型化合物以及用于预防 PCa 的临床相关植物化学组合。