Jaceosidin inhibits cell viability and induces apoptosis in non-small cell lung cancer by inhibiting the Ras/Raf/MEK/ERK and Akt pathways.

Abstract

Non-small cell lung cancer (NSCLC) remains a major health challenge due to its poor prognosis and low 5-year survival rate; therefore, the development of efficient and less toxic anti-NSCLC therapies is of great importance. The present study aimed to investigate the anti-survival and pro-apoptotic effects of Jaceosidin, a flavonoid, on human NSCLC cells and to uncover its underlying mechanism. Cell viability, cell cycle progression and apoptosis were assess using the MTS assay and flow cytometry, and protein expression was analyzed by western blot analysis. The results showed that Jaceosidin significantly reduced A549 cell viability in a dose-dependent manner, whereas it exhibited significantly lower cytotoxicity against 293T cells. In addition, cell cycle distribution analysis demonstrated that A549 cell treatment with Jaceosidin induced S-phase cell cycle arrest, which was accompanied by p21 upregulation. Jaceosidin also enhanced cell apoptosis, and upregulated cleaved-poly-ADP ribose polymerase and cleaved-caspase-3 expression in a dose-dependent manner. Furthermore, Jaceosidin promoted the release of cytochrome c (cyto-c) from mitochondria into the cytoplasm, as detected by digitonin-based fractionation and western blotting, thus resulting in increased cytosolic cyto-c levels. Finally, Jaceosidin significantly reduced the expression of Ras and Raf, and the downstream signaling molecules ERK1/2 and Akt, which may suppress A549 cell viability and enhance apoptosis. Overall, the current study suggested that Jaceosidin exerts potential anti-NSCLC activity with tumor-selective cytotoxicity through inhibiting the Ras/Raf/MEK/ERK and Akt pathways, and activating both intrinsic mitochondrial and extrinsic apoptotic pathways, thus representing a promising natural product candidate for future NSCLC therapy.