VE-822 Enhanced Cisplatin Chemotherapy Effects on Head and Neck Squamous Cell Carcinoma Drug-resistant Cells

Abstract

Purpose: The study aimed to assess the effect of p-ATR inhibitor VE-822 in the combination chemotherapy with cisplatin of head and neck squamous cell carcinoma and to explore the possible mechanism.

Methods: The DNA damage levels were determined by comet assay and western blot experiments in cisplatin-resistant and sensitive cell lines. The IC50 value changes after combination treatment with VE-822 in cisplatin sensitive and resistant cell lines were detected by the CCK-8 test. The effects of VE-822 combined with cisplatin on proliferation ability, colony formation ability, migration ability, cell apoptosis and cell cycle changes were observed in vitro. In vivo, the combination treatment effect was verified in the subcutaneous xenograft models of nude mice. Besides, the mechanism of VE-822 assisting cisplatin in chemotherapy was explored by comet assay, western blotting and immunohistochemical experiments.

Results: The increased expression of the p-ATR protein was related to the DNA damage repair pathway in head and neck squamous cell carcinoma cisplatin-resistant cells. VE-822 inhibited cell proliferation, colony formation and migration abilities and improved the cisplatin chemotherapeutic effects in subcutaneous xenograft models of nude mice by inhibiting the p-ATR expression and blocking DNA damage repair pathway.

Conclusions: The p-ATR expression increased in head and neck squamous cell carcinoma cisplatinresistant cells. VE-822 significantly enhanced the therapeutic effect in cisplatin resistant head and neck squamous cell carcinoma by inhibiting p-ATR expression in vivo and in vitro.

Keywords: Chemotherapy; VE-822; cisplatin; cisplatin resistance; head and neck squamous cell carcinoma; p-ATR.