title: 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.
authors.affiliation: Department of Surgery, Chungnam National University Hospital, Daejeon 301‑721, Republic of Korea.
authors.forename: Hyun Su
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Surgery, Chungnam National University Hospital, Daejeon 301‑721, Republic of Korea.
authors.forename: Jun Beom
authors.initials: JB
authors.lastname: Park
authors.affiliation: Surgical Oncology Research Lab, Chungnam National University Hospital, Daejeon 301‑721, Republic of Korea.
authors.forename: Myung Sun
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Surgical Oncology Research Lab, Chungnam National University Hospital, Daejeon 301‑721, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Cha
authors.affiliation: Department of Surgery, Chungnam National University Hospital, Daejeon 301‑721, Republic of Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Surgery, Chungnam National University Hospital, Daejeon 301‑721, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Sul
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D015398:Signal Transduction; D013274:Stomach Neoplasms; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D014315:Triterpenes; C113861:corosolic acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D005472:Fluorouracil