Arsenic sulfide reverses cisplatin resistance in non-small cell lung cancer in vitro and in vivo through targeting PD-L1.

Background Recent studies have found that programmed death ligand 1 (PD-L1) might be involved in chemotherapy resistance in non-small cell lung cancer (NSCLC). Arsenic sulfide (As4 S4 ) has been recognized to have antitumor activities and enhance the cytotoxic effect of chemotherapy drugs. In this study, we aimed to verify the relationship between PD-L1 and cisplatin (DDP) resistance and identify whether As4 S4 could reverse DDP resistance through targeting PD-L1 in NSCLC. Methods The effect of As4 S4 and DDP on cell proliferation and apoptosis was investigated in NSCLC cell lines. The expression of p53 and PD-L1 proteins was measured by western blotting analysis. The levels of miR-34a-5p, miR-34a-3p and PD-L1 in cells were measured by real-time qPCR analysis. Mouse xenograft models were established by inoculation with A549/DDP (DDP-resistant) cells. Results Depletion of PD-L1 inhibited DDP resistance in A549/DDP and H1299/DDP cells. As4 S4 was capable of sensitizing A549/DDP cells to DDP by enhancing apoptosis. As4 S4 upregulated p53 expression and downregulated PD-L1 expression in A549/DDP cells. As4 S4 increased miR-34a-5p level in A549/DDP cells. Inhibition of p53 by PFT-α partially restored the levels of PD-L1 and miR-34a-5p. Pretreatment with PFT-α suppressed the apoptosis rate induced by cotreatment of As4 S4 and DDP in A549/DDP cells. Cotreatment of DDP and As4 S4 notably reduced the tumor size when compared with DDP treatment alone in vivo. Conclusions Upregulation of PD-L1 was correlated with DDP resistance in NSCLC cells. Mechanistic analyses indicated that As4 S4 might sensitize NSCLC cells to DDP through targeting p53/miR-34a-5p/PD-L1 axis.