Ovarian cancer (OVCA) is a fatal malignancy of women with highest case to death ratio among gynecological cancers. OVCA differs from other malignancies that it mainly disseminates locally in the peritoneal and abdominal cavity. Thus, factors in tumor microenvironment play critical roles in tumor progression as well as prevention of OVCA metastasis. Innate immune cells are members of tumor microenvironment and first responders to a developing tumor. However, tumor suppresses anti-tumor immune responses by secreting immunosuppressive factors, which in most cases, shift anti-tumor functions of innate immune cells to pro-tumor roles favoring tumor growth. Natural killer (NK) cells are a member of innate immunity with cytotoxic functions necessary to eliminate a growing tumor. However, our preliminary studies showed that progression of ovarian tumors to late stages was associated with the inhibition of NK cell infiltration to the tumor vicinity. Our preliminary studis further showed that this tumor-induced inhibition of intra-tumor NK cell infiltration was mediated by shedding of major histocompatibility complex class I related chain A (MICA) expressed on the surface of malignant cells. MICA is a ligand of NK cell receptor NKG2D. Upon binding with MICA, NKG2D activates NK cells for cytotoxic activities. Shedding of MICA by the tumor from its surface prevents NK cells to recognize the tumor cells, thus, the tumor escapes cytotoxic effects of NK cells. Dietary supplementation of hens (with or without OVCA) with Ashwagandha root powder in our preliminary study showed inhibition of tumor progression and reduced incidence of new OVCA cases. Ashwagandha is an herb used in traditional medicine as anti-stressor and inflammatory agent. Proposed study seeks to confirm these preliminary observations in a large cohort of hens by two Specific Aims.
Aim 1 will determine the efficacy of Ashwagandha in increasing the influx of intra-tumoral NK cells and thus enhancing ovarian tumoricidal role of NK cells.
Aim 2 will determine the length of exposure to dietary Ashwagandha supplementation required to maintain a long- term anti-tumor activities of NK cells. Successful accomplishment of the proposed study will generate noble information and will be helpful for a longer study and/or an early phase clinical study to examine the role of Ashwagandha in enhancing ovarian tumoricidal functions of NK cells.

Public Health Relevance

Ovarian cancer (OVCA) is a lethal disease of women with highest rate of death among gynecological cancers. OVCA is an aggressive malignancy with non-specific symptoms at early stage, thus, in most cases, it is detected at late stages when the 5-year survival rate of patients is <20% as opposed to .80% when it is detected at early stage. Ovarian tumors progresses to advance stages by inhibiting anti-tumor immune function. Herbs and their products have long been used in traditional medicine to ameliorate stress and chronic and acute inflammation. Our preliminary study showed that Ashawagandha (Winter Cherry) root powder when supplemented in the diet of chicken, a preclinical model of spontaneous OVCA prevented tumor progression and incidence of new cases by enhancing the antitumor activities of a member of immune system (natural killer cells). Proposed study is the first systematic study to test the effects of dietary Ashwagandha supplementation on the enhancement of anti-tumor function of natural killer cells. Accomplishment of this project will establish preventive measures to inhibit ovarian tumor induced suppression of natural killer cell functions. Because of the similarities of incidence and progression of these diseases between human and hen, information to be generated from the successful completion of this project will be translated immediately for a clinical study. Success of this study will save globally lives of 200,000 women/year from ovarian cancer, reduce prophylactic surgery or improve quality of lives of patients and reduce public healthcare costs remarkably.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Chemo/Dietary Prevention Study Section (CDP)
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Kim, Young S
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Rush University Medical Center
Schools of Medicine
United States
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