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 (As(4)S(4)) 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 As(4)S(4) could reverse DDP resistance through targeting PD‐L1 in NSCLC. METHODS: The effect of As(4)S(4) 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. As(4)S(4) was capable of sensitizing A549/DDP cells to DDP by enhancing apoptosis. As(4)S(4) upregulated p53 expression and downregulated PD‐L1 expression in A549/DDP cells. As(4)S(4) 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 As(4)S(4) and DDP in A549/DDP cells. Cotreatment of DDP and As(4)S(4) 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 As(4)S(4) might sensitize NSCLC cells to DDP through targeting p53/miR‐34a‐5p/PD‐L1 axis.