Dietary components have become very attractive agents for cancer prevention. Toward this end, we envision the use of dietary components to modulate innate immune cell function with the goal of cancer prevention. Natural killer (NK) cells can be modulated to cure acute myeloid leukemia (AML), and NK cell activity is correlated with relapse-free survival in AML. AML is a disease that primarily affects older adults: the median age at diagnosis is over 65, and the 5-year survival rate remains under 10%. Elderly AML patients are less able to tolerate therapies effective in younger patients, such as intensive chemotherapy and allogeneic stem cell transplantation. Therefore, novel, less toxic, approaches to prevent AML and AML relapse represent an unmet therapeutic need. Our preliminary data show that phyllanthusmin C (PL-C), a diphyllin lignan isolated from edible plants, can enhance NK cell activity. PL-C enhances human NK cell interferon-gamma (IFN-g) production via upregulation of the NF-kB signaling component, p65. This finding is consistent with our in vivo data, showing that treatment with PL-C can prolong the survival of the mice bearing AML in our syngeneic orthotopic animal model. We also found that PL-C can be detected in murine plasma 30 minutes after administration via oral gavage at a dose of 200 mg/kg. Based on these data, we hypothesize that PL-C originated from edible plants can enhance NK cell tumoricidal activity, and thus may possess therapeutic efficacy in the prevention of cancers including AML. We propose to test our hypothesis through the following three Aims:
Aim 1 is to determine whether PL-C regulates NK cell cytotoxicity against AML cells in vitro;
Aim 2 is to investigate the mechanisms by which PL-C enhances NK cell anti-tumor activity.
Aim 3 is to study the preclinical efficacy of PL-C in the prevention of AML in vivo. To our knowledge, this is the first time that a lignan-based dietary component from an edible plant has been demonstrated to specifically and significantly enhance human NK cell function. As such, our study may open a new avenue for cancer prevention. Because PL-C is a compound that comes from an edible plant, this preclinical study has relatively strong potential for translation into the clinic as Phse I, Phase II, and then Phase III chemoprevention trials to be initiated following completion of this study. Therefore, not only is our study innovative and significant, but it is also highly translational.

Public Health Relevance

Dietary components play a critical role in cancer prevention. Acute myeloid leukemia (AML) is a disease that primarily affects elderly adults with a median age over 65 at diagnosis. Over the past 40 years, the 5-year survival rate for these elderly patients has remained under 10%. The goal of this application is to conduct preclinical research on the use of a dietary component to enhance natural killer cell activity for the prevention of AML.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Chemo/Dietary Prevention Study Section (CDP)
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Kim, Young S
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Ohio State University
Internal Medicine/Medicine
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United States
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Freud, Aharon G; Mundy-Bosse, Bethany L; Yu, Jianhua et al. (2017) The Broad Spectrum of Human Natural Killer Cell Diversity. Immunity 47:820-833
Victor, Aaron R; Nalin, Ansel P; Dong, Wenjuan et al. (2017) IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-?B. J Immunol 199:2333-2342
Pan, Pan; Kang, Siwen; Wang, Youwei et al. (2017) Black Raspberries Enhance Natural Killer Cell Infiltration into the Colon and Suppress the Progression of Colorectal Cancer. Front Immunol 8:997
Teng, Kun-Yu; Han, Jianfeng; Zhang, Xiaoli et al. (2017) Blocking the CCL2-CCR2 Axis Using CCL2-Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model. Mol Cancer Ther 16:312-322
Chen, L; Mao, H; Zhang, J et al. (2017) Targeting FLT3 by chimeric antigen receptor T cells for the treatment of acute myeloid leukemia. Leukemia 31:1830-1834
Scoville, Steven D; Mundy-Bosse, Bethany L; Zhang, Michael H et al. (2016) A Progenitor Cell Expressing Transcription Factor ROR?t Generates All Human Innate Lymphoid Cell Subsets. Immunity 44:1140-50
Chen, Luxi; Yu, Jianhua (2016) Modulation of Toll-like receptor signaling in innate immunity by natural products. Int Immunopharmacol 37:65-70
Zhao, Shuting; Zhang, Lingling; Han, Jianfeng et al. (2016) Conformal Nanoencapsulation of Allogeneic T Cells Mitigates Graft-versus-Host Disease and Retains Graft-versus-Leukemia Activity. ACS Nano 10:6189-200
Ren, Yulin; Yu, Jianhua; Kinghorn, A Douglas (2016) Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones. Curr Med Chem 23:2397-420
Freud, Aharon G; Keller, Karen A; Scoville, Steven D et al. (2016) NKp80 Defines a Critical Step during Human Natural Killer Cell Development. Cell Rep 16:379-391

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