Nivolumab effectively inhibit platinum-resistant ovarian cancer cells via induction of cell apoptosis and inhibition of ADAM17 expression

摘要

OBJECTIVE: Nivolumab is an anti-PD-1 (anti-programmed death-1) monoclonal antibody. It has achieved an overall response rate of 17% in Phase 1 clinical trial for patient with platinum-resistant ovarian cancer (PROC). However, its underlying mechanism has not been fully explored yet. The aim of the study is to investigate the efficiency of nivolumab to inhibit PROC cells and its possible mechanism. MATERIALS AND METHODS: Firstly, methylthiazolyl tetrazolium bromide (MTT) assay was performed to determine the IC50 values of cisplatin in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. The results showed that IC50 (half maximal inhibitory concentration) values of cisplatin were significantly decreased in a time-dependent manner in A2780, A2780/DDP, SKOV3, and SKOV3/DDP cells. Secondly, MMT assay was used once again to measure anti-tumor effects of nivolumab in A2780/DDP cells. The results showed that anti-tumor effects of nivolumab increased in a dose- and time-dependent manner. Thirdly, A2780/DDP cells were treated with nivolumab in combination with cisplatin for 48 h. RESULTS: The results demonstrated that nivolumab increased the anti-tumor effects of cisplatin in A2780/DDP cells. Notably, the combined treatment effectively reversed cisplatin resistance in PROC cells. Also, nivolumab induced cell apoptosis and cell-cycle arrest in G0/G1 phase in PROC cells. FACS and Western blot were performed to measure cell apoptosis and Bcl-2 and Bax expression respectively. The results showed that combined treatment significantly increased cell apoptosis rate, down-regulated Bcl-2, and unregulated Bax expression in PROC cells. Additionally, the expression levels of ADAM17 were significantly decreased in a dose-dependent manner in PROC cells, which were treated with nivolumab. CONCLUSIONS: Therefore, all the results demonstrated that the combined treatment with nivolumab and cisplatin effectively inhibited PROC cells via induction of cell apoptosis and inhibition of ADAM17 expression.