Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3.
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.
Leeman-Neill
Rebecca J
RJ
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Wheeler
Sarah E
SE
Singh
Shivendra V
SV
Thomas
Sufi M
SM
Seethala
Raja R
RR
Neill
Daniel B
DB
Panahandeh
Mary C
MC
Hahm
Eun-Ryeong
ER
Joyce
Sonali C
SC
Sen
Malabika
M
Cai
Quan
Q
Freilino
Maria L
ML
Li
Changyou
C
Johnson
Daniel E
DE
Grandis
Jennifer R
JR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D029744:Commiphora; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D008517:Phytotherapy; D028321:Plant Preparations / Q000494:pharmacology; D011282:Pregnenediones / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D028321:Plant Preparations; D011282:Pregnenediones; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C023617:pregna-4,17-diene-3,16-dione; D000069347:Erlotinib Hydrochloride; D000068818:Cetuximab; D002945:Cisplatin