Enhancing NK Cell Activity by Dietary Diphyllin Lignans for Cancer Prevention

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DESCRIPTION (provided by applicant): 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-γ) 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.