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.

项目总结 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的策略。 用于预防前列腺癌(PCA)。在美国，PCA是最常见的被诊断为非 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)]在耗尽细胞ATP水平和抑制生长/存活方面非常有效 小鼠(HMVP2，来源于HiMyc小鼠的PCA细胞系)和人(DU145，C4-2B)PCA细胞系。 这两种组合对体外培养的PCa细胞的生长都有协同抑制作用，也有协同作用。 在同种异体移植瘤模型中，在饮食中给药时抑制HMVP2细胞的生长。此外， PCa肿瘤细胞代谢组学分析表明，有效的植物化学结合减少 谷氨酰胺摄取可能有助于增强观察到的肿瘤生长抑制活性。我们有 最近获得了更多的增效组合，使用了以依诺酮(ENO)为基础的两层筛选 铅化合物涉及ATP耗竭和谷氨酰胺摄取的抑制。以下组合之一(ENO+ 水飞蓟宾)被进一步测试并被证明在体内协同抑制HMVP2 PCa细胞的生长 这一方法的原则证明。在本提案中，我们将测试以下假设： 某些天然化合物，可以通过它们消耗细胞ATP和阻断细胞的能力来识别 谷氨酰胺摄取将成为治疗前列腺癌的高效、协同的化学预防药物。我们还将测试 假设有效的组合将有能力抑制特定的致癌作用 代谢和信号通路对前列腺癌的发展和进展非常重要。具体目标 1：评估天然化合物的组合是否具有协同和选择性抑制的能力 PCa细胞系的生长特性；2：检查在特定情况下确定的最有效的药物组合 目标1：它们对致癌信号通路的影响(例如，STAT3、src、nFκB、AMPK、mTOR和 CXCL12/CXCR4)以及代谢途径的变化(例如谷氨酰胺摄取和利用，血脂谱， 等)；3：检查选定的天然化合物组合预防前列腺癌的能力 两个相关的前列腺癌小鼠模型(HiMyc和PTENpcko)的发展/进展；以及4：继续 筛选更大的天然化合物文库以鉴定新的热门化合物和筛选化合物 联合用药协同消耗细胞ATP水平和阻断前列腺癌谷氨酰胺摄取的能力 细胞系。拟议研究的完成将导致采用新的方法来确定 用于癌症化学预防研究的植物化学物质，并可能导致一种或多种新的 以及临床上相关的预防前列腺癌的植物化学组合。