1. Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3.
- Author
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Leeman-Neill RJ, Wheeler SE, Singh SV, Thomas SM, Seethala RR, Neill DB, Panahandeh MC, Hahm ER, Joyce SC, Sen M, Cai Q, Freilino ML, Li C, Johnson DE, and Grandis JR
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Apoptosis drug effects, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Cell Cycle drug effects, Cell Line, Tumor, Cell Survival drug effects, Cetuximab, Cisplatin pharmacology, Cisplatin therapeutic use, Commiphora, Drug Synergism, Erlotinib Hydrochloride, Female, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Humans, Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors, Mice, Mice, Nude, Neoplasm Transplantation, Plant Preparations pharmacology, Quinazolines pharmacology, Quinazolines therapeutic use, STAT3 Transcription Factor antagonists & inhibitors, Carcinoma, Squamous Cell drug therapy, Head and Neck Neoplasms drug therapy, Phytotherapy, Pregnenediones pharmacology
- Abstract
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 EC(50)s ranging from 5 to 8 microM. 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)-1alpha 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-1alpha provide a biologic rationale for further clinical investigation of this compound in the treatment of HNSCC.
- Published
- 2009
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