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Lupeol Suppresses Cisplatin-Induced Nuclear Factor-B Activation in Head and Neck Squamous Cell Carcinoma and Inhibits Local Invasion and Nodal Metastasis in an Orthotopic Nude Mouse Model

Departments of ¹ Surgery and ² Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong, China; ³ Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁴ Tumor Immunology Programme, D010 German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Anthony P.W. Yuen, Department of Surgery, The University of Hong Kong Queen Mary Hospital, 102 Pokfulam Road, Hong Kong. Phone: 852-2855-3641; Fax: 852-2819-3464; E-mail: pwyuen{at}hkucc.hku.hk.

A poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients is commonly associated with the presence of regional metastasis. Cisplatin-based chemotherapy concurrent with radiation therapy is commonly used in the treatment of locally advanced HNSCC. However, the result is dismal due to common acquisition of chemoresistance and radioresistance. Epidemiologic studies have shown the importance of dietary substances in the prevention of HNSCC. Here, we found that lupeol, a triterpene found in fruits and vegetables, selectively induced substantial HNSCC cell death but exhibited only a minimal effect on a normal tongue fibroblast cell line in vitro. Down-regulation of NF-B was identified as the major mechanism of the anticancer properties of lupeol against HNSCC. Lupeol alone was not only found to suppress tumor growth but also to impair HNSCC cell invasion by reversal of the NF-B–dependent epithelial-to-mesenchymal transition. Lupeol exerted a synergistic effect with cisplatin, resulting in chemosensitization of HNSCC cell lines with high NF-B activity in vitro. In in vivo studies, using an orthotopic metastatic nude mouse model of oral tongue squamous cell carcinoma, lupeol at a dose of 2 mg/animal dramatically decreased tumor volume and suppressed local metastasis, which was more effective than cisplatin alone. Lupeol exerted a significant synergistic cytotoxic effect when combined with low-dose cisplatin without side effects. Our results suggest that lupeol may be an effective agent either alone or in combination for treatment of advanced tumors. [Cancer Res 2007;67(18):8800–9]

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