Sclareol induces cell cycle arrest and ROS‐mediated apoptosis and ferroptosis in lung adenocarcinoma cells

Abstract Sclareol (SC) has shown significant anticancer activity against breast and colon cancers among others. However, its ability to precipitate similar anticancer effects in lung cancer has yet to be investigated. To address this issue, SC‐treated lung adenocarcinoma cells (A549) were assessed for viability and functional competence as well as the expression of genes related to apoptosis and cell cycling. Our results demonstrated that SC treatment inhibited A549 cell clonogenic features and reduced their migration and invasion potential in a dose‐dependent manner. Mechanistically, SC treatment downregulated the expression of cyclin D1 and survivin and upregulated that of p21 and p16, which was associated with a significant increase in the percentage of SubG0 cells. SC treatment is also associated with the induction of both the extrinsic and intrinsic apoptotic pathways, as evidenced by the increased expression and splitting of PARP1 and procaspases 3 and 9 and the reduced expression of antiapoptotic proteins Bcl‐2 and Bcl‐xL. Increased cell death in SC‐treated cells is likely to have resulted from the induction of ferroptosis as suggested by the reduced expression of FPN and the inhibition of the anti‐ferroptosis regulator GPX4. In conclusion, the data presented here suggest that SC can reduce lung carcinoma cell growth and metastasis and promote cell death.