Department of Molecular Medicine
 

[ default picture ] Michael  J. WargovichPh.D.

Professor


Profile and Contact Information | Research | Laboratory


RESEARCH

 

Research Program


The Wargovich Lab
Our laboratory investigates ways to prevent various cancers. Our focus is on the chemoprevention of cancer - “Chemoprevention” is a discipline of cancer research that is less than 20 years old and embraces the idea that cancer can be prevented or precancers can be inhibited from progressing to cancer by the use of natural compounds or pharmaceuticals. We study cancer biology using a number of human cancer cell lines and also utilize novel animal models for colon cancer. Natural products can include substances from wine and green tea, fruits and vegetables, compounds in herbs and spices, vitamins and minerals, and dietary supplements. The lab has an interest in both terrestrial and marine botanicals. Via the pharmaceutical route, drug development has led to the discovery of compounds like tamoxifen for the prevention of breast cancer, aspirin for colon cancer.

What We Do
Our laboratory is located in the McDermott Clinical Science building. We concentrate on the search for natural agents that inhibit the process of chronic inflammation, believed to increase the risk for future cancer. Habitual intake of NSAIDS (Non-steroidal anti-inflammatory drugs) is associated with reduced risk for common forms of cancer, including colon cancer. Because of the toxicity associated with pharmaceutical NSAIDs, we are examining botanical agents that may interfere with chronic inflammation. These include compounds from green tea, the herbal supplements ginkgo and ginseng, and traditional medicines from other cultures. We’re convinced that chronic, clinically undetectable inflammation at the cellular level enables many of the common cancers to form and grow. Tumors corrupt inflammatory pathways to survive. We are looking at ways to prevent this.

Ethnobotanical Research

  • West Africa & Australia

  • We are conducting research to identify cancer prevention agents in traditional medicines used in West Africa. For several years this research has taken us to the West African nation of the Republic of Guinea. One of traditional medicines used there is the bark of Senegal mahogany (Khaya senegalensis) which appears to inhibit the COX-2 enzyme in human colorectal cell lines studied in the lab (we now have a sustainable source of this bark from northern Australia). We have initiated global collaborative studies to investigate natural products from other cultures to establish whether there is potential for the prevention of colon cancer.

  • Brazil - in collaboration with Empbrapa Clima Temperado in Pelotas

  • Here we are investigating the Brazilian pitanga fruit (Eugenia uniflora), a fruit native to Brazil that undergoes a ripening process ranging from yellow to orange, and red to purple berries. We hypothesize that this unique chemistry involves carotenoid and anthocyanadin biosynthesis and the fruits should prove to be very high in antioxidant and anti-inflammatory potential – possibly very useful in cancer prevention.

  • Colombia - In collaboration with Pontifica Universidad Javeriana –Bogota

  • Our laboratory has begun studies in collaboration with researchers in Bogata on the Colombian native fruits as sources of cancer prevention agents. Fresh fruit from tropical plants is widely consumed in Colombia, and our initial studies are focused on borojo, native Colombian grapes, and starfruit extracts.

  • India - in collaboration with Nisarga Biotech, Sartara

  • With Dr. Susan Reed in the College of Dental Medicine at the Medical University of South Carolina we are exploring the use of an Ayurvedic herbal formulated in a special mouthwash to alleviate the side effects of radiotherapy to the head and neck region of cancer patients. The mouthwash is designed to reduce the side effects of oral mucositis. We use supercritical CO2 extracts of the leaves of Azadirachta indica.


    Cancer Chemoprevention – Mechanistic Research


  • Epigenetic regulation of RXR alpha via inhibition DNMTs and HDACs

  • Our studies on green tea polyphenols suggest epigenetic regulation of regulatory genes in colon cancer progression. We are investigating the role of EGCG on the silencing of the RXRα gene in the APCMin+/ mouse, an animal model for colon cancer. We are studying the role EGCG has in regulating epigenetic mechanisms constituents such as - DNMTs, HDACs, and HATs in early onset of colon tumorigenesis. Along with mechanistic research, we are studying if EGCG can synergistically enhance the effects of current clinical therapies.

  • Molecular Prevention of Colitis with EGCG and Vitamin D3

  • The hypothesis underlying this project ties to together the importance of low serum vitamin D levels in colitis patients, our research on RXRα which is silenced in colon cancer, and the vitamin D receptor (VDR). In this project we hypothesize that RXRα may be silenced in colitis due to upregulaton of DNA methyltransferase enzymes (DNMTs). This forecasts that VDR may be impaired due to the silencing of its heterodimer, RXRα. We are using the AOM/DSS model for colitis and testing whether EGCG (which restores RXRα expression) facilitates VDR stimulation by Vitamin D3, causing remission of colitis.

     

    Selected Publications

    1. Moseley VR, Morris J, Knackstedt RW, Wargovich MJ. Green Tea Polyphenol Epigallocatechin 3-Gallate, Contributes to the Degradation of DNMT3A and HDAC3 in HCT 116 Human Colon Cancer Cells. Anticancer Res. 2013 Dec;33(12):5325-33.
    2. Thompson IM Jr, Cabang AB, Wargovich MJ. Future directions in the prevention of prostate cancer. Nat Rev Clin Oncol. 2014 Jan;11(1):49-60.
    3. Knackstedt R, Shaoli S, Moseley V, Wargovich M. The Importance of the Retinoid X Receptor Alpha in Modulating Inflammatory Signaling in Acute Murine Colitis. Dig Dis Sci. 2013 Oct 22.
    4. Knackstedt RW, Moseley VR, Sun S, Wargovich MJ. Vitamin D receptor and retinoid X receptor α status and vitamin D insufficiency in models of murine colitis. Cancer Prev Res (Phila). 2013 Jun;6(6):585-93.
    5. Luo H, Yang A, Schulte BA, Wargovich MJ, Wang GY. Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage. PLoS One. 2013;8(3):e60065.
    6. Wallace K, Hill EG, Lewin DN, Williamson G, Oppenheimer S, Ford ME, Wargovich MJ, Berger FG, Bolick SW, Thomas MB, Alberg AJ. Racial disparities in advanced-stage colorectal cancer survival. Cancer Causes Control. 2013 Mar;24(3):463-71.
    7. Knackstedt R, Moseley VR, Sun S, and Wargovich MJ: (2013) Vitamin D receptor and retinoid X receptor alpha status and vitamin D insufficiency in models of murine colitis. Cancer Prev Res (Phila). [Epub ahead of print.]
    8. Poudyal D, Le PM, Davis T, Hofseth AB, Chumanevich A, Chumanevich AA, Wargovich MJ, Nagarkatti M, Nagarkatti PS, Windust A, and Hofseth LJ: (2012) Hexane fraction of American ginseng suppresses colitis and colon cancer--response. Cancer Prev Res. 5: 983.
    9. Sokolosky ML and Wargovich MJ: (2012) Homeostatic imbalance and colon cancer: the dynamic epigenetic interplay of inflammation, environmental toxins, and chemopreventive plant compounds. Front Oncol.2: 57.
    10. Poudyal D, Le PM, Davis T, Hofseth AB, Chumanevich A, Chumanevich AA, Wargovich MJ, Nagarkatti M, Nagarkatti PS, Windust A, and Hofseth LJ: (2012) A hexane fraction of American ginseng suppresses mouse colitis and associated colon cancer: anti-inflammatory and proapoptotic mechanisms. Cancer Prev Res (Phila) 5(4): 685-96.
    11. Wargovich MJ, Brown VR, and Morris J: (2010) Aberrant crypt foci: the case for inclusion as a biomarker for colon cancer. Cancers. 2: 1705-16.
    12. Volate SR, Muga SJ, Issa AY, Nitcheva D, Smith T, and Wargovich MJ: (2009) Epigenetic modulation of the retinoid X receptor alpha by green tea in the azoxymethane-Apc Min/+ mouse model of intestinal cancer. Mol Carcinog. 48(10): 920-33.
    13. Volate S, Hudson R, Wang D, Muga S, and Wargovich M: (2009) TJ-41 induces apoptosis and potentiates the apoptotic effects of 5-FU in breast cancer cell lines. J Oncol. 2009: 895381.
    14. Zhang H, Tan J, Vanderveer D, Wang X, Wargovich MJ, and Chen F: (2009) Khayanolides from African mahogany Khaya senegalensis (Meliaceae): a revision. Phytochemistry. 70(2): 294-9.