Adjudin synergizes with paclitaxel and inhibits cell growth and metastasis by regulating the sirtuin 3–Forkhead box O3a axis in human small‐cell lung cancer

Abstract

Background Small‐cell lung cancer (SCLC), a malignant tumor, 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. However, the mechanism on SCLC was unclear. Methods We investigated the potential mechanism and effect of Adjudin on SCLC both in vitro and in vivo. Results An SCLC xenograft model showed that Adjudin inhibited tumor growth and was significantly synergetic with paclitaxel (in vitro as well). Cell Counting Kit‐8 assays, flow cytometric analysis and western blotting showed that Adjudin effectively suppressed SCLC cell proliferation by 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 sirtuin 3 (SIRT3)–Forkhead box O3a (FOXO3a) pathway. Downregulating SIRT3 or FOXO3a significantly attenuated Adjudin‐induced anticancer effects. Furthermore, higher expression of SIRT3 and FOXO3a were positively correlated, and both were associated with longer survival in lung cancer patients. Conclusion Overall, the present study is the first to show that Adjudin synergizes with paclitaxel and inhibits cell growth and metastasis by regulating the SIRT3–FOXO3a axis in SCLC; thus, Adjudin has great potential to be an anticancer agent.

Keywords

• Adjudin
• Forkhead box O3a
• paclitaxel
• sirtuin 3
• small‐cell lung cancer