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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：
9765960
负责人：
John DiGiovanni
金额：
$ 50.2万
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/9765960
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 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.

项目总结