Corosolic acid enhances 5-fluorouracil-induced apoptosis against SNU-620 human gastric carcinoma cells by inhibition of mammalian target of rapamycin

Abstract

5-Fluorouracil (5-FU), one of the oldest anticancer therapeutic agents, is increasingly being administered in cancer chemotherapy. In the present study, the anticancer effects of 5-FU combined with corosolic acid (CRA) were determined in SNU-620 human gastric carcinoma cells and the underlying mechanisms were examined. A combination treatment of 5-FU and CRA inhibited the viability of cells additively. Furthermore, apoptotic activity following combination treatment was found to be stronger than that of the single treatments, as observed using an Annexin V/propidium iodide assay. The protein level of Bcl-2 was decreased significantly by the combination treatment, whereas the protein level of Bim was increased. The release of mitochondrial cytochrome c was increased as a result of the combination treatment, however, the combination treatment additively increased caspase-3 and poly-(ADP-ribose) polymerase cleavages. Additionally, the mammalian target of rapamycin (mTOR) signaling pathway, which is highly activated in gastric cancer, was regulated by 5-FU and CRA, and additive mTOR/eukaryotic translation initiation factor 4E-binding protein 1 (4-EBP1) inhibition was observed with the combination treatment. Additional rapamycin treatment along with the combination treatment of 5-FU and CRA showed a more marked inhibition of mTOR/4-EBP1 in the cells, as well as increased apoptosis and antiproliferation. Thus, these data indicate that CRA enhances the anticancer activities of 5-FU via mTOR inhibition in SNU-620 human gastric carcinoma cells.