Curcumin Enhances the Effect of Cisplatin in Suppression of Head and Neck Squamous Cell Carcinoma via Inhibition of IKKβ Protein of the NFκB Pathway

Previous experiments have shown that curcumin or cisplatin treatment suppresses growth of head and neck squamous cell carcinoma (HNSCC). To study the potential cooperative effect of both agents, two HNSCC cell lines were treated with curcumin or cisplatin alone or in combination. In vivo studies consisted of intravenous tail vein injection of liposomal curcumin, with intraperitoneal cisplatin, into nude mice growing xenograft HNSCC tumors. Introduction of curcumin and suboptimal concentrations of cisplatin showed a significant suppressive effect compared with treatment with either agent alone. Reduced expression of cyclin D1, I kappa B alpha, phospho-I kappa B alpha, and IKK beta occurred in cisplatin- and curcumin-treated cell lines. Confocal microscopy showed expression of IKK beta in the nucleus of the cell lines. Chromatin immunoprecipitation assay on DNA isolated from IKK beta immunoprecipitated samples showed PCR amplification of interleukin-8 promoter sequences, a binding site of NF kappa B, indicating an interaction between IKK beta and NF kappa B. Curcumin inhibited IKK beta in the cytoplasm and nucleus, leading to reduced NF kappa B activity, with no effect on phospho-AKT. In vivo studies showed significant growth inhibition of xenograft tumors treated with a combination of liposomal curcumin and cisplatin. The suppressive effect of curcumin was mediated through inhibition of cytoplasmic and nuclear IKK beta, resulting in inhibition of NF kappa B activity. Cisplatin treatment led to cellular senescence, indicating an effect mediated by p53 activation. The mechanisms of the two agents through different growth signaling pathways suggest potential for the clinical use of subtherapeutic doses of cisplatin in combination with curcumin, which will allow effective suppression of tumor growth while minimizing the toxic side effects of cisplatin. Mol Cancer Ther; 9(10); 2665-75. (C) 2010 AACR.