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

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. Human HNSCC cell lines and the xenograft animal model of HNSCC were used to test the effects of honokiol treatment. 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. 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 RJ ，Cai Q ，Joyce SC ，Thomas SM ，Bhola NE ，Neill DB ，Arbiser JL ，Grandis JR ... -  《-》

Preclinical modeling of EGFR inhibitor resistance in head and neck cancer.

Quesnelle KM ，Wheeler SE ，Ratay MK ，Grandis JR ... -  《-》

Combined targeting of epidermal growth factor receptor, signal transducer and activator of transcription-3, and Bcl-X(L) enhances antitumor effects in squamous cell carcinoma of the head and neck.

Boehm AL ，Sen M ，Seethala R ，Gooding WE ，Freilino M ，Wong SM ，Wang S ，Johnson DE ，Grandis JR ... -  《-》

Targeting Stat3 abrogates EGFR inhibitor resistance in cancer.

EGF receptor (EGFR) is upregulated in most epithelial cancers where signaling through EGFR contributes to cancer cell proliferation and survival. The limited clinical efficacy of EGFR inhibitors suggests that identification of resistance mechanisms may identify new pathways for therapeutic targeting. STAT3 is upregulated in many cancers and activated via both EGFR-dependent and -independent pathways. In the present study, we tested the consequences of STAT3 inhibition in EGFR inhibitor-resistant head and neck squamous cell carcinoma (HNSCC) and bladder cancer models to determine whether STAT3 blockade can enhance responses to EGFR targeting. pSTAT3 expression was assessed in human HNSCC tumors that recurred following cetuximab treatment. Cetuximab-sensitive and -resistant cell lines were treated with a STAT3 decoy to determine EC(50) concentrations and the effects on STAT3 target gene expression by Western blotting. In vivo assays included evaluation of antitumor efficacy of STAT3 decoy in cetuximab-sensitive and -resistant models followed by immunoblotting for STAT3 target protein expression. Targeting STAT3 with a STAT3 decoy reduced cellular viability and the expression of STAT3 target genes in EGFR inhibitor resistance models. The addition of a STAT3 inhibitor to EGFR blocking strategies significantly enhanced antitumor effects in vivo. Biopsies from HNSCC tumors that recurred following cetuximab treatment showed increased STAT3 activation compared with pretreatment biopsies. These results suggest that STAT3 activation contributes to EGFR inhibitor resistance both in HNSCC and bladder cancer where concomitant targeting of STAT3 may represent an effective treatment strategy.

Sen M ，Joyce S ，Panahandeh M ，Li C ，Thomas SM ，Maxwell J ，Wang L ，Gooding WE ，Johnson DE ，Grandis JR ... -  《-》

Honokiol inhibits the growth of head and neck squamous cell carcinoma by targeting epidermal growth factor receptor.

Singh T ，Gupta NA ，Xu S ，Prasad R ，Velu SE ，Katiyar SK ... -  《Oncotarget》