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Prevention and Treatment of Head and Neck Cancer with Natural Compound Inhibitors of STAT3

Leeman, Rebecca (2008) Prevention and Treatment of Head and Neck Cancer with Natural Compound Inhibitors of STAT3. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Leeman, RebeccaRJL16@pitt.eduRJL16
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWells, Alanwellsa@upmc.eduAHW6
Committee MemberGrandis, Jennifer
Committee MemberLi,
Committee MemberDeFrances, Mariedefrancesmc@upmc.eduMCD14
Committee MemberSingh, Shivendrasinghs@upmc.eduSVS2
Date: 18 December 2008
Date Type: Completion
Defense Date: 11 December 2008
Approval Date: 18 December 2008
Submission Date: 13 December 2008
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: HIF-1 alpha; honokiol; STAT3; guggulsterone; head and neck cancer
Other ID:, etd-12132008-204045
Date Deposited: 10 Nov 2011 20:10
Last Modified: 19 Dec 2016 14:38


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