Department of Stomatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Department of Stomatology, Shanghai Jing-An Dental Clinic, Shanghai, 200040, China.
Curr Cancer Drug Targets. 2023;23(6):482-495. doi: 10.2174/1568009623666230206143216.
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.
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 . , 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.
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.
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 and .
本研究旨在评估 p-ATR 抑制剂 VE-822 联合顺铂化疗对头颈部鳞状细胞癌的疗效，并探讨可能的机制。
通过彗星实验和 Western blot 实验检测顺铂耐药和敏感细胞系中 DNA 损伤水平。通过 CCK-8 试验检测 VE-822 联合顺铂处理后敏感和耐药细胞系中 IC50 值的变化。观察 VE-822 联合顺铂对增殖能力、集落形成能力、迁移能力、细胞凋亡和细胞周期变化的影响。在裸鼠皮下移植瘤模型中验证联合治疗效果。此外，通过彗星实验、Western blot 和免疫组化实验探讨 VE-822 协助顺铂化疗的机制。
p-ATR 蛋白的高表达与头颈部鳞状细胞癌顺铂耐药细胞的 DNA 损伤修复途径有关。VE-822 通过抑制 p-ATR 表达和阻断 DNA 损伤修复途径，抑制细胞增殖、集落形成和迁移能力，并提高裸鼠皮下移植瘤模型中的顺铂化疗效果。
头颈部鳞状细胞癌顺铂耐药细胞中 p-ATR 表达增加。VE-822 通过抑制 p-ATR 表达增强了顺铂耐药头颈部鳞状细胞癌的治疗效果。
