A novel nitric oxide-donor-ferulic acid hybrid inhibits proliferation and metastasis of human lung cancer A549 cells via regulation of multiple signaling pathways

Lung cancer is one of the most common malignancies as well as an increasing cause of cancer-related deaths. Nitric oxide (NO)-donor-ferulic acid (FA) hybrids, in our previous study, were designed and synthesized, which exhibited positive anti-cancer activities, especially one compound labelled as FXS-3. In this study, an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were performed and revealed the inhibitory effect of FXS-3 on the proliferation and metastasis of human lung cancer A549 cells. The further flow cytometry assay showed that FXS-3 induced apoptosis of A549 cells by inducing cell cycle arrest at the G0/G1 phase. The trans-well migration and Matrigel invasion assays revealed that FXS-3 inhibited the migration and invasion of A549 cells. By the western blotting analysis, FXS-3 increased the expression of B-cell lymphoma-2 (Bcl-2) associated X protein (Bax)/Bcl-2 ratio, inhibited matrix metalloproteinase (MMP)-2 and MMP-9, and suppressed the mitogen-activated protein kinase (MAPK), AKT/mechanistic target of rapamycin (mTOR), as well as mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. The subsequent A549 xenograft-bearing mouse model and tail vein injection of A549 cells induced pulmonary tumor metastasis model showed that FXS-3 significantly restrained the tumor growth and metastasis. In conclusion, FXS-3 might inhibit proliferation and metastasis of human lung cancer A549 cells by inhibiting MAPK, AKT/mTOR and MEK/ERK signaling pathways, which provides important scientific basis for the development of anti-cancer drugs about NO-donor-FA hybrids.