Honokiol inhibits epidermal growth factor receptor signaling and enhances the antitumor effects of epidermal growth factor receptor inhibitors

Rebecca J. Leeman-Neill, Quan Cai, Sonali C. Joyce, Sufi M. Thomas, Neil E. Bhola, Daniel Neill, Jack L. Arbiser, Jennifer R. Grandis

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Experimental Design: 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 (EC50) values ranging from 3.3 to 7.4 μmol/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-XL 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.

Original languageEnglish (US)
Pages (from-to)2571-2579
Number of pages9
JournalClinical Cancer Research
Volume16
Issue number9
DOIs
StatePublished - May 1 2010

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Epidermal Growth Factor Receptor
Growth
STAT3 Transcription Factor
Heterografts
Cell Line
Carcinoma, squamous cell of head and neck
honokiol
Annexin A5
Cyclin D1
United States Food and Drug Administration
Mitogen-Activated Protein Kinases
Drug Resistance
Neoplasms
Research Design
Therapeutics
Animal Models
Apoptosis
Staining and Labeling
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Honokiol inhibits epidermal growth factor receptor signaling and enhances the antitumor effects of epidermal growth factor receptor inhibitors. / Leeman-Neill, Rebecca J.; Cai, Quan; Joyce, Sonali C.; Thomas, Sufi M.; Bhola, Neil E.; Neill, Daniel; Arbiser, Jack L.; Grandis, Jennifer R.

In: Clinical Cancer Research, Vol. 16, No. 9, 01.05.2010, p. 2571-2579.

Research output: Contribution to journalArticle

Leeman-Neill, Rebecca J. ; Cai, Quan ; Joyce, Sonali C. ; Thomas, Sufi M. ; Bhola, Neil E. ; Neill, Daniel ; Arbiser, Jack L. ; Grandis, Jennifer R. / Honokiol inhibits epidermal growth factor receptor signaling and enhances the antitumor effects of epidermal growth factor receptor inhibitors. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 9. pp. 2571-2579.
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