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 demonstrated a significant suppressive effect compared to treatment with either agent alone. Reduced expression of cyclin D1, IkBα, phospho-IkBα and IKKβ occurred in cisplatin and curcumin treated cell lines. Confocal microscopy showed expression of IKKβ in the nucleus of the cell lines. Chromatin immunoprecipitation (ChiP) assay on DNA isolated from IKKβ immunoprecipitated samples showed PCR amplification of IL-8 promoter sequences, a binding site of NFκB, indicating an interaction between IKKβ and NFκB. Curcumin inhibited IKKβ in the cytoplasm and nucleus, leading to reduced NFκB activity, with no effect on pAKT. In vivo studies demonstrated significant growth inhibition of xenograft tumors treated with a combination of liposomal curcumin and cisplatin. Curcumin's suppressive effect was mediated through inhibition of cytoplasmic and nuclear IKKβ, resulting in inhibition of NFκB activity. Cisplatin treatment led to cellular senescence, indicating an effect mediated by p53 activation. The two agents’ mechanisms 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 cisplatin's toxic side effects.
Keywords: Head and neck squamous cell carcinoma, Liposomal Curcumin, Cisplatin, Growth suppression, Nuclear factor kB