A Novel Curcumin Analog (H-4073) Enhances the Therapeutic Efficacy of Cisplatin Treatment in Head and Neck Cancer

Chemotherapy constitutes the standard modality of treatment for localized head and neck squamous cell carcinomas (HNSCC). However, many patients fail to respond and relapse after this treatments due to the acquisition of chemoresistance. Therefore, there is an urgent need to develop novel drugs that could reverse the resistant phenotype. Curcumin, the constituent of the spice turmeric has been shown to have anti-inflammatory, anti-oxidant and anti-proliferative properties in several tumor types. However, use of curcumin has been limited due to its poor bio-absorption. Recently, a novel class of curcumin analogs, based on diarylidenylpiperidones (DAP), has been developed by incorporating a piperidone link to the beta-diketone structure and fluoro substitutions on the phenyl groups. In this study, we evaluated the effectiveness of H-4073, a parafluorinated variant of DAP, using both in vitro and in vivo head and neck cancer models. Our results demonstrate that H-4073 is a potent anti-tumor agent and it significantly inhibited cell proliferation in all the HNSCC cell lines tested in a dose-dependent manner. In addition, pretreatment of cisplatin-resistant HNSCC cell lines with H-4073 significantly reversed the chemo-resistance as observed by cell viability assay (MTT), apoptosis assay (Annexin V binding) and cleaved caspase-3 (Western blot). H-4073 mediated its anti-tumor effects by inhibiting JAK/STAT3, FAK, Akt and VEGF signaling pathways that play important roles in cell proliferation, migration, survival and angiogenesis. In the SCID mouse xenograft model, H-4073 significantly enhanced the anti-tumor and anti-angiogenesis effects of cisplatin, with no added systemic toxicity. Interestingly, H-4073 inhibited tumor angiogenesis by blocking VEGF production by tumor cells as well as directly inhibiting endothelial cell function. Taken together, our results suggest that H-4073 is a potent anti-tumor agent and it can be used to overcome chemotherapy resistance in HNSCC.