Combined treatment with cisplatin and the tankyrase inhibitor XAV-939 increases cytotoxicity, abrogates cancer-stem-like cell phenotype and increases chemosensitivity of head-and-neck squamous-cell carcinoma cells

Abstract

Cancer stem-like cells (CSCs) were reported to be linked with tumorigenesis, metastasis and resistant to chemo and radiotherapy in head and neck squamous cell carcinoma (HNSCC). In this study we investigated the role of CSCs in chemoresistance and abrogation of CSC mediated chemoresistance by combinatorial treatment with cisplatin and small molecule tankyrase inhibitor XAV-939. Two cisplatin-resistant HNSCC cells were generated by stepwise dose incremental strategy. We evaluated the chemoresistance, sphere forming capacity, extent of DNA damage and repair capacity in parental and cisplatin-resistant HNSCC cells. Furthermore, the abrogation of CSC mediated chemoresistance was evaluated in HNSCC cells with XAV-939 alone and in combination with cisplatin. It was observed that cisplatin-resistant HNSCC cell lines exhibited increase in chemoresistance, CSC phenotype and increased DNA repair capacity. We observed that combination of cisplatin and XAV-939 acts synergistically to abrogate chemoresistance by increasing DNA damage. Molecular docking study also revealed similar binding region that could contribute towards synergy predictions between cisplatin and XAV939. In conclusion, this study elucidated that combination of cisplatin and XAV-939 exerted cytotoxic and genotoxic effect to abrogate CSC mediated chemoresistance in HNSCC in synergistic manner.