The first two authors contributed equally to this work.
Cancer Cell Biology
Synergistic inhibition of head and neck tumor growth by green tea (−)-epigallocatechin-3-gallate and EGFR tyrosine kinase inhibitor
Article first published online: 10 JUN 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 123, Issue 5, pages 1005–1014, 1 September 2008
How to Cite
Zhang, X., Zhang, H., Tighiouart, M., Lee, J. E., Shin, H. J., Khuri, F. R., Yang, C. S., Chen, Z. and Shin, D. M. (2008), Synergistic inhibition of head and neck tumor growth by green tea (−)-epigallocatechin-3-gallate and EGFR tyrosine kinase inhibitor. Int. J. Cancer, 123: 1005–1014. doi: 10.1002/ijc.23585
- Issue published online: 17 JUN 2008
- Article first published online: 10 JUN 2008
- Manuscript Accepted: 27 FEB 2008
- Manuscript Received: 8 JAN 2008
- National Cancer Institute. Grant Numbers: R01 CA112643, U01 CA101244
- NCI Head and Neck SPORE. Grant Number: P50 CA128613
- Georgia Cancer Coalition Distinguished Scholar Award
- squamous cell carcinoma of the head and neck;
One of the mechanisms of the antitumor activity of green tea (−)-epigallocatechin-3-gallate (EGCG) is associated with its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways. We investigated whether combining EGCG with the EGFR-tyrosine kinase inhibitor (EGFR-TKI) erlotinib may augment erlotinib-induced cell growth inhibition of squamous cell carcinoma of the head and neck (SCCHN) in a mouse xenograft model. In vitro studies with 5 head and neck cancer cell lines revealed that synergistic cell growth inhibition by the combination of EGCG and erlotinib was associated with significantly greater inhibition of pEGFR and pAKT, increased activation of caspases 9, 3 and PARP compared to the inhibition induced by EGCG or erlotinib alone. Erlotinib inhibited phosphorylation of EGFR, stabilizing EGFR at the plasma membrane, whereas EGCG induced EGFR internalization and ubiquitin-degradation, ultimately undermining EGFR signaling. The efficacy of the combination treatment was investigated with nude mice (n = 25) orally gavaged with vehicle control, EGCG, erlotinib or the combination at the same doses for 7 days, followed by subcutaneous injection with Tu212 cells. Animals were continuously administered the agents 5 days weekly for 7 weeks. The combined treatment resulted in significantly greater inhibition of tumor growth and delayed tumor progression as a result of increased apoptosis, decreased cell proliferation and reduced pEGFR and pAKT compared to the single agent treatment groups. Our results suggest a synergistic antitumor effect of a combined treatment with EGCG and erlotinib, and provide a promising regimen for future chemoprevention and treatment of SCCHN. © 2008 Wiley-Liss, Inc.