Program Director

Principal Investigator

Awardee Organization

University Of Texas At Austin
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Identification of Natural Compound Combinations for Prevention of Prostate Cancer

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 noncutaneous 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.


  • Hackman GL, Collins M, Lu X, Lodi A, DiGiovanni J, Tiziani S. Predicting and Quantifying Antagonistic Effects of Natural Compounds Given with Chemotherapeutic Agents: Applications for High-Throughput Screening. Cancers. 2020 Dec 10;12. (12). PMID: 33322034
  • Saha A, Hamilton-Reeves J, DiGiovanni J. White adipose tissue-derived factors and prostate cancer progression: mechanisms and targets for interventions. Cancer metastasis reviews. 2022 Sep;41(3):649-671. Epub 2022 Aug 4. PMID: 35927363
  • Choudhury FK, Hackman GL, Lodi A, Tiziani S. Stable Isotope Tracing Metabolomics to Investigate the Metabolic Activity of Bioactive Compounds for Cancer Prevention and Treatment. Cancers. 2020 Aug 3;12. (8). PMID: 32756373
  • Lu X, Hackman GL, Saha A, Rathore AS, Collins M, Friedman C, Yi SS, Matsuda F, DiGiovanni J, Lodi A, Tiziani S. Metabolomics-based phenotypic screens for evaluation of drug synergy via direct-infusion mass spectrometry. iScience. 2022 Apr 7;25(5):104221. doi: 10.1016/j.isci.2022.104221. eCollection 2022 May 20. PMID: 35494234
  • Gries P, Rathore AS, Lu X, Chiou J, Huynh YB, Lodi A, Tiziani S. Automated Trimethyl Sulfonium Hydroxide Derivatization Method for High-Throughput Fatty Acid Profiling by Gas Chromatography-Mass Spectrometry. Molecules (Basel, Switzerland). 2021 Oct 15;26. (20). PMID: 34684827