Adjudin Synergizes With Paclitaxel And Inhibits Cell Growth And Metastasis By Regulating The SIRT3-FOXO3a Axis In Human Small-cell Lung Cancer

BACKGROUND: Small-cell lung cancer(SCLC),a malignant tumour,is usually widely metastatic when diagnosed.The lack of important therapeutic clinical advances makes it difficult to treat.Previous studies showed that Adjudin had anticancer effects in many other human cancers,and it was synergetic with cisplatin in non–small cell lung cancer(NSCLC).However,the mechanism on SCLC was unclear.METHODS and RESULTS: We investigated the potential mechanism and effect of Adjudin on SCLC both in vitro and in vivo.An SCLC xenograft model showed that Adjudin inhibited tumour growth and was significantly synergetic with paclitaxel(in vitro as well).CCK-8(Cell Counting Kit-8)assays,flow cytometric analysis and Western blotting revealed that Adjudin effectively suppressed SCLC cell proliferation via inducing S phase arrest and caspase-dependent apoptosis.Moreover,transwell and scratch assays showed that Adjudin also effectively inhibited migration and invasion.Furthermore,Adjudin activated the SIRT3-FOXO3 a pathway.Downregulating SIRT3 or FOXO3 a significantly attenuated Adjudin-induced anticancer effects.Furthermore,higher expression of SIRT3 and FOXO3 a were positively correlated,and both were associated with longer survival in lung cancer patients.CONCLUSION: Overall,the present study is the first to illustrate that Adjudin synergizes with paclitaxel and inhibits cell growth and metastasis by regulating the SIRT3-FOXO3 a axis in SCLC;thus,Adjudin has great potential to be an anticancer agent.