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

• 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
• 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

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.

项目摘要 拟议研究的总体目标是使用理化的组合制定新型策略 预防前列腺癌（PCA）。在美国，PCA是最常被诊断出的非 - 皮肤癌和癌症相关死亡率的第二大主要原因估计为164,690 2018年的新病例和估计29,430例死亡（美国癌症协会）。我们最近发现 天然化合物与ursolic Acid（UA）的几种组合[即UA +姜黄素（Curc）和 UA +白藜芦醇（RES）]在耗尽细胞ATP水平并抑制生长/存活方面非常有效 这两种小鼠（HMVP2，源自HIMYC小鼠的PCA细胞系）和人（DU145，C4-2B）PCA细胞系。 这两种组合都在体外产生了对PCA细胞生长的协同抑制作用，并且在协同上也是协同的 饮食中施用时，在同种异体移植肿瘤模型中抑制HMVP2细胞的生长。此外， PCA肿瘤细胞的代谢组学分析表明，有效的生理组合降低了 谷氨酰胺的摄取可能导致观察到的肿瘤生长抑制活性增强。我们有 最近，使用带有依诺克隆（Eno）的两层屏幕获得了其他协同组合 铅化合物涉及ATP耗竭和抑制谷氨酰胺摄取。这些组合之一（Eno + 进一步测试了硅脂），并在体内协同抑制HMVP2 PCA细胞的生长是进一步的 这种方法的原理证明。在此提案中，我们将检验以下假设 某些可以通过其完全细胞ATP和阻断能力来识别的天然化合物 谷氨酰胺的摄取将是PCA的高效，协同的化学预防剂。我们还将测试 有效组合将具有抑制特定致癌的能力的假设 代谢和信号通路对PCA的发展和进展很重要。具体目标 是：1：评估天然化合物的组合，以协同和有选择地抑制其能力 PCA细胞系的生长特性； 2：检查特异性鉴定的代理的最有效组合 AIM 1对它们对致癌信号通路的影响（例如STAT3，SRC，NFκB，AMPK，MTOR和MTOR和 CXCL12/CXCR4）以及代谢途径的变化（例如，谷氨酰胺摄取和利用率，脂质曲线，脂质曲线， ETC）; 3：检查选定的天然化合物组合的效果，以防止PCA PCA的两个相关小鼠模型（HIMYC和PTENPCKO）的开发/进展；和4：继续 筛选较大的天然化合物库，以识别新型的热门最佳化合物和屏幕化合物 结合它们能够协同细胞的细胞ATP水平并阻止PCA中谷氨酰胺的吸收能力的组合 细胞系。拟议研究的完成将导致新的方法来识别组合 用于癌症化学预防研究的植物化学物质，可能导致鉴定一个或多个新型 以及预防PCA的临床相关物理组合。