This Senior Scientist Award application will provide partial salary support and release time for the candidate to foster the careers of 5 junior investigators whose research interests focus on alcohol research. A specific mentoring plan is provided that is augmented by several institutional resources. The award will also allow the candidate to conduct and expand his research on the role of alcohol in cancer progression, to promote awareness of alcohol as a risk factor for cancer, and to develop collaborative opportunities in these areas. Alcohol abuse is a worldwide problem and is associated with increased incidence of various cancers;however its role in cancer progression is not well understood. The research plan addresses cancer progression and is based on preliminary data that chronic alcohol consumption decreases metastasis of murine melanoma. Interferon gamma (IFN-g) produced by natural killer (NK) and NKT cells and possibly memory T cells is essential to control metastasis of melanoma. Preliminary data indicate that alcohol consumption significantly increases IFN-g producing NKT and T memory cells. Alcohol consuming mice die prematurely even though metastasis is inhibited and the mechanisms associated for this decrease in survival will be investigated. It is hypothesized that the antimetastatic effect of chronic alcohol consumption is due to increased production of IFN-g by NKT and memory T cells. It is further hypothesized that alcohol consumption decreases survival through a combination of effects on altering T cell survival, hypoglycemia, and oxidative stress. To test these hypotheses, we propose the following specific aims: 1. Determine the contributions of NKT cells and T cells to the mechanism by which alcohol consumption inhibits melanoma metastasis 2. Determine the effect of alcohol on metastasis of other animal tumor models. 3. Determine the mechanisms associated with decreased survival of alcohol consuming, melanoma-bearing mice. Alcohol, 20% w/v in the drinking water, will be given to female C57BL/6, NKT knockout, IFN-g knockout, and nude mice to assess the mechanisms associated with inhibition of melanoma metastasis. Experimental and spontaneous metastasis assays also will be used to examine the effects of alcohol on metastasis of prostate and lung cancer. Flow cytometric and ELISA assays will be used to determine lymphocyte populations, surface and intracellular marker expression, cytokine producing cells, and cytokine concentrations.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Scientist Award (K05)
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Special Emphasis Panel (ZAA1-CC (11))
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Jung, Kathy
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Washington State University
Internal Medicine/Medicine
Schools of Pharmacy
United States
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Hopkins, Mandi M; Zhang, Zhihong; Liu, Ze et al. (2016) Eicosopentaneoic Acid and Other Free Fatty Acid Receptor Agonists Inhibit Lysophosphatidic Acid- and Epidermal Growth Factor-Induced Proliferation of Human Breast Cancer Cells. J Clin Med 5:
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Zhang, Hui; Zhang, Faya; Zhu, Zhaohui et al. (2015) Chronic alcohol consumption enhances iNKT cell maturation and activation. Toxicol Appl Pharmacol 282:139-50
Hopkins, Mandi M; Feng, Xiaoxing; Liu, Mengwei et al. (2015) Inhibition of the transient receptor potential melastatin-2 channel causes increased DNA damage and decreased proliferation in breast adenocarcinoma cells. Int J Oncol 46:2267-76
Feng, Xiaoxing; Koh, David W (2013) Inhibition of poly(ADP-ribose) polymerase-1 or poly(ADP?ribose) glycohydrolase individually, but not in combination, leads to improved chemotherapeutic efficacy in HeLa cells. Int J Oncol 42:749-56
Meadows, Gary G (2012) Diet, nutrients, phytochemicals, and cancer metastasis suppressor genes. Cancer Metastasis Rev 31:441-54
Zhang, Hui; Zhu, Zhaohui; Meadows, Gary G (2012) Chronic alcohol consumption impairs distribution and compromises circulation of B cells in B16BL6 melanoma-bearing mice. J Immunol 189:1340-8
Feng, Xiaoxing; Zhou, Yiran; Proctor, Alicia M et al. (2012) Silencing of Apoptosis-Inducing factor and poly(ADP-ribose) glycohydrolase reveals novel roles in breast cancer cell death after chemotherapy. Mol Cancer 11:48

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