Head and neck squamous cell carcinoma (HNSCC) is a commonly occurring malignancy associated with severe morbidity, persistently high mortality rates, frequent recurrence, and the appearance of second primary tumors (SPTs). A great need exists, therefore, for new therapies, including complementary and preventive approaches to treating HNSCC. Signal transducer and activator of transcription (STAT)-3, an oncogenic transcription factor, shows promise as an important therapeutic target in the treatment of HNSCC. The current study focuses on the STAT3-targeting activities of two natural compounds, guggulsterone and honokiol, and investigation of their antitumor activity in HNSCC. Guggulsterone, a compound contained in the resin of the Commiphora mukul plant, used in Indian Ayurvedic medicine, is widely available as a dietary supplement and associated with few side effects. Honokiol is a naturally-occurring compound that has been used in traditional Chinese medicine and is derived from the plant, Magnolia officinalis. Both compounds have been shown to have anticancer activity in various models and to inhibit nuclear factor kappa B (NF kappa B), an oncogenic transcription factor. NF kappa B and STAT3 interact with one another in various ways. Therefore, we hypothesized that guggulsterone and/or honokiol might be useful in targeting STAT3. Both compounds inhibited growth and invasiveness and induced apoptosis in HNSCC cell lines, in addition to decreasing levels of phosphotyrosine STAT3, and, for guggulsterone, total STAT3. Guggulsterone was also found to cause cell cycle arrest and to target hypoxia-inducible factor (HIF)-1 alpha, a potential therapeutic target whose expression is correlated with poor clinical outcome in HNSCC. Guggulsterone-induced growth inhibition relied partly on its ability to inhibit STAT3. Both compounds enhanced the activities of current HNSCC therapies and modestly inhibited tumor growth in the xenograft model of HNSCC. To test the chemopreventive potential of STAT3 and epidermal growth factor receptor (EGFR) inhibition, a study administering Guggulipid, a guggulsterone-containing nutraceutical, or erlotinib, an EGFR-targeting tyrosine kinase inhibitor (TKI) to mice treated orally with a carcinogen is currently underway. Our results so far suggest that guggulsterone and honokiol-mediated inhibition of STAT3 and guggulsterone-mediated inhibition of HIF-1 alpha provide a biologic rationale for further clinical investigation of these compounds as complementary and preventive treatments for HNSCC.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12132008-204045 |
| Date | 18 December 2008 |
| Creators | Leeman, Rebecca |
| Contributors | Shivendra Singh, PhD, Jennifer R. Grandis, MD, Luyuan Li, PhD, Marie DeFrances, MD, PhD, Alan Wells, MD, DMS |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12132008-204045/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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