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Carcinogenesis Advance Access originally published online on September 16, 2009
Carcinogenesis 2009 30(11):1848-1856; doi:10.1093/carcin/bgp211
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3

Rebecca J. Leeman-Neill1, Sarah E. Wheeler1, Shivendra V. Singh2, Sufi M. Thomas3, Raja R. Seethala1, Daniel B. Neill4, Mary C. Panahandeh3, Eun-Ryeong Hahm2, Sonali C. Joyce3, Malabika Sen3, Quan Cai3, Maria L. Freilino3, Changyou Li2, Daniel E. Johnson2 and Jennifer R. Grandis13,*

1 Department of Pathology
2 Department of Pharmacology
3 Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15261
4 Heinz College, School of Public Policy and Management, Carnegie Mellon University, Pittsburgh, PA 15213

* To whom correspondence should be addressed. 200 Lothrop Street, Eye and Ear Institute, Suite 500, Pittsburgh, PA; Tel: 412-647-5280; Fax: 412-383-5409; Email: grandisjr{at}upmc.edu

Treatment of human head and neck squamous cell carcinoma (HNSCC) cell lines with guggulsterone, a widely available, well-tolerated nutraceutical, demonstrated dose-dependent decreases in cell viability with EC50s ranging from 5 to 8 µM. Guggulsterone induced apoptosis and cell cycle arrest, inhibited invasion and enhanced the efficacy of erlotinib, cetuximab and cisplatin in HNSCC cell lines. Guggulsterone induced decreased expression of both phosphotyrosine and total signal transducer and activator of transcription (STAT)-3, which contributed to guggulsterone's growth inhibitory effect. Hypoxia-inducible factor (HIF)-1{alpha} was also decreased in response to guggulsterone treatment. In a xenograft model of HNSCC, guggulsterone treatment resulted in increased apoptosis and decreased expression of STAT3. In vivo treatment with a guggulsterone-containing natural product, Guggulipid, resulted in decreased rates of tumor growth and enhancement of cetuximab's activity. Our results suggest that guggulsterone-mediated inhibition of STAT3 and HIF-1{alpha} provide a biologic rationale for further clinical investigation of this compound in the treatment of HNSCC.

Abbreviations: EGFR, epidermal growth factor receptor; FXR, farnesoid X receptor; HNSCC, head and neck squamous cell carcinoma; HIF, hypoxia-inducible factor; NF{kappa}B, nuclear factor kappa B; siRNA, small interfering RNA; STAT, signal transducer and activator of transcription

Received February 12, 2009; revised July 2, 2009; accepted August 1, 2009.


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