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

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-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.