Honokiol inhibits epidermal growth factor receptor signaling and enhances the antitumor effects of epidermal growth factor receptor inhibitors.
OBJECTIVE
This study aimed to investigate the utility of honokiol, a naturally occurring compound, in the treatment of head and neck squamous cell carcinoma (HNSCC) as well as its ability to target the epidermal growth factor receptor (EGFR), a critical therapeutic target in HNSCC, and to enhance the effects of other EGFR-targeting therapies.


METHODS
Human HNSCC cell lines and the xenograft animal model of HNSCC were used to test the effects of honokiol treatment.


RESULTS
Honokiol was found to inhibit growth in human HNSCC cell lines, with 50% effective concentration (EC(50)) values ranging from 3.3 to 7.4 micromol/L, and to induce apoptosis, as shown through Annexin V staining. These effects were associated with inhibition of EGFR signaling, including downstream inhibition of mitogen-activated protein kinase, Akt, and signal transducer and activator of transcription 3 (STAT3), and expression of STAT3 target genes, Bcl-X(L) and cyclin D1. Furthermore, honokiol enhanced the growth inhibitory and anti-invasion activity of the EGFR-targeting agent erlotinib. Although HNSCC xenograft models did not show significant inhibition of in vivo tumor growth with honokiol treatment alone, the combination of honokiol plus cetuximab, a Food and Drug Administration-approved EGFR inhibitor for this malignancy, significantly enhanced growth inhibition. Finally, HNSCC cells rendered resistant to erlotinib retained sensitivity to the growth inhibitory effects of honokiol.


CONCLUSIONS
These results suggest that honokiol may be an effective therapeutic agent in HNSCC, in which it can augment the effects of EGFR inhibitors and overcome drug resistance.
Leeman-Neill
Rebecca J
RJ
Department of Pathology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Cai
Quan
Q
Joyce
Sonali C
SC
Thomas
Sufi M
SM
Bhola
Neil E
NE
Neill
Daniel B
DB
Arbiser
Jack L
JL
Grandis
Jennifer R
JR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017705:Lignans / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D000068818:Cetuximab; D004365:Drugs, Chinese Herbal; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D017705:Lignans; D011799:Quinazolines; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
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