Licoricidin Enhances Gemcitabine-induced Cytotoxicity in Osteosarcoma Cells by Suppressing the Akt and NF-κB Signal Pathways

Osteosarcoma (OS) is the most common bone malignancy in children and adolescents. Combined treatments of anti-cancer drugs can remarkably improve chemotherapeutic outcomes. Gemcitabine and licoricidin both have potential anti-tumor activity in several cancers. However, the combined therapeutic efficiency of gemcitabine and licoricidin for OS has not been explored. Here, we found that licoricidin or gemcitabine inhibited OS cell viability in a dose-dependent manner. Cotreatment with licoricidin and gemcitabine enhanced gemcitabine-induced cytotoxicity in OS cells. Licoricidin suppressed activation of the Akt and nuclear factor-kappa B (NF-κB) pathways. Gemcitabine had no effect on Akt signal, but facilitated the activation of NF-κB signal in OS cells. Moreover, combined treatment of licoricidin and gemcitabine markedly curbed the activation of Akt and NF-κB pathways in OS cells. Inhibition of the Akt and NF-κB pathways enhanced gemcitabine-induced cytotoxicity in OS cells. In vivo assay further manifested that licoricidin enhanced gemcitabine-induced cytotoxicity in tumor xenograft models of OS via inactivation of the Akt and NF-κB pathways. In conclusion, licoricidin enhanced gemcitabine-induced cytotoxicity in OS cells by inactivation of the Akt and NF-κB pathways in vitro and in vivo.