Tumour growth suppressive effect of arsenic trioxide in squamous cell lung carcinoma

Lung cancer is one of the top cancer killers worldwide. Squamous cell lung carcinoma (SCC) accounts for the second most common subtype of patients diagnosed with nonsmall cell lung carcinoma. At present, doublet platinum based chemotherapy remains the only first line treatment option in SCC. Therefore, new therapeutic approaches are urgently needed. Arsenic trioxide (ATO) is an old traditional Chinese medicine which shows anticancer effects in hematological diseases including acute promyelocytic leukemia partially via apoptosis. Recently, the effects of ATO in lung adenocarcinoma and small cell lung carcinoma have been studied while such effects in SCC are still unknown. Hence, the aim of this study is to study the tumor suppressive effect of ATO in SCC. Among a panel of four SCC cell lines, SK-MES-1 and SW900 SCC cell lines were found to be relatively sensitive to ATO with IC50 values within clinically reachable concentration and thus they were chosen for subsequent experiments. Then, the underlying mechanisms of ATO-induced cytotoxicity were studied. There were increasing number of late apoptotic cells and elevation of cell proportion with mitochondrial membrane depolarization in SK-MES-1 cells but not in SW900 cells upon ATO treatment. ATO induced G2/M arrest in both SK-MES-1 and SW900 cells. Downregulation of XIAP and Bcl-2 were detected in SW900 and SK-MES-1 cells respectively with ATO, while Bak was upregulated in SW900 cells. In addition, expression of cleaved PARP was elevated in SK-MES-1 cells, and upregulation of cleaved caspase 3 was observed in both cell lines following ATO treatment. ATO might also have antiproliferative effect, via reduced E2F1 expression in both cell lines. However, thymidylate synthase and RRM1 were suppressed in ATO-treated SK-MES-1 cells only. Based on the in vitro data, ATO induced apoptosis partially via intrinsic pathway in SK-MES-1 cells, but via extrinsic pathway in SW900 cells. Nude mice xenograft model was developed using SW900 cells in order to determine the in vivo anti-cancer effects of ATO. Inhibition of tumour growth was observed with 7.5 mg/kg ATO treatment, associated with downregulation of Bcl-2 and E2F1 protein expression and presence of apoptotic bodies. Sulindac is a non-steroid anti-inflammatory drug. It was reported that synergistic effect was observed when combining with ATO. As such, combination of ATO and sulindac was studied in SCC cell lines. However, the cytotoxic effect could not be enhanced in such combination when compared with ATO alone. In summary, ATO suppressed tumor growth in SCC partially via activation of apoptosis and inhibition of cell proliferation in vitro and in vivo. Further study about the underlying mechanisms is warranted.published_or_final_versionMedicineMasterMaster of Philosoph