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开发新的策略，使用植物化学物质的组合 预防前列腺癌（PCa）。在美国，PCa是最常诊断的非- 皮肤癌是男性癌症相关死亡的第二大原因，估计有164，690人 2018年新增病例和估计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（HMVP 2，来源于HiMyc小鼠的PCa细胞系）和人（DU 145，C4-2B）PCa细胞系。 这两种组合在体外产生了对PCa细胞生长的协同抑制，并且还协同地 当在饮食中给药时，在同种异体移植肿瘤模型中抑制HMVP 2细胞的生长。此外，委员会认为， 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 谷氨酰胺摄取，这可能有助于观察到的增强的肿瘤生长抑制活性。我们有 最近获得了另外的协同组合，其使用两层筛选，以依诺沙星（ENO）作为 涉及ATP消耗和谷氨酰胺摄取抑制先导化合物。这些组合之一（ENO + 进一步测试了水飞蓟宾），并显示其协同抑制HMVP 2 PCa细胞的体内生长， 证明了这种方法的原理。在本提案中，我们将检验以下假设： 某些天然化合物，可以通过它们消耗细胞ATP和阻断 谷氨酰胺摄取将是PCa的高效协同化学预防剂。我们还将测试 有效组合将具有抑制特定致癌性的能力的假设 代谢和信号通路对PCa的发展和进展很重要。具体目标 1：评价天然化合物的组合协同和选择性抑制 PCa细胞系的生长特性; 2：检查在特异性PCR中鉴定的最有效的药物组合。 目的1：它们对致癌信号通路的影响（例如，Stat3、Src、NFκB、AMPK、mTOR和 CXCL 12/CXCR 4）以及代谢途径变化（例如，谷氨酰胺摄取和利用，脂质分布， 3：检查所选天然化合物组合预防PCa的能力的效果 在PCa的两种相关小鼠模型（HiMyc和PTENpcko）中的发展/进展;和4：继续 筛选更大的天然化合物库以鉴定新的热门化合物并筛选化合物 它们的组合协同消耗细胞ATP水平和阻断PCa中谷氨酰胺摄取的能力 细胞系完成拟议的研究将导致新的方法来确定组合 植物化学物质的癌症化学预防研究，并可能导致一个或多个新的鉴定 和临床相关的植物化学组合用于预防PCa。