title: Berberine sensitizes rapamycin‑mediated human hepatoma cell death in vitro.
abstract: Rapamycin is clinically used as an immunosuppressant. Increasing evidence suggests that rapamycin has an important inhibitory role in the development and progression of different types of cancer and that it is a promising candidate for cancer chemotherapy. Berberine is an isoquinoline alkaloid isolated from medicinal plant species, which has been used in traditional Chinese medicine with no significant side effects. Recent research has demonstrated that berberine has anticancer activity against various types of cancer, mediated through the suppression of mammalian target of rapamycin (mTOR). The present study aimed to investigate the in vitro synergistic anticancer effect of combined treatment of rapamycin at various concentrations (0, 10, 50, 100 and 200 nM) and berberine (62.5 µM) in SMMC7721 and HepG2 hepatocellular carcinoma (HCC) cell lines, and the potential underlying molecular mechanism. The combined use of rapamycin and berberine was found to have a synergistic cytotoxic effect, with berberine observed to maintain the cyotoxic effect of rapamycin on HCC cells at a lower rapamycin concentration. Moreover, the cells treated with the combination of the two agents exhibited significantly decreased protein levels of phosphorylated (p)‑p70S6 kinase 1 (Thr389), the downstream effector of mTOR, compared with the cells treated with rapamycin or berberine alone. Furthermore, overexpression of cluster of differentiation (CD) 147, a transmembrance glycoprotein associated with the anticancer effects of berberine, was found to upregulate p‑mTOR expression and inhibit cell death in SMMC7721 cells co‑treated with rapamycin and berberine. In conclusion, the findings of the present study suggest that the combined use of rapamycin and berberine may improve HCC therapy through synergistically inhibiting the mTOR signaling pathway, which is at least in part, mediated through CD147.
authors.affiliation: Laboratory of Cell Biology and Translational Medicine, Institute of Basic Medical Science, X'ian Medical University, Xi'an, Shaanxi 710021, P.R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Guo
authors.affiliation: Laboratory of Cell Biology and Translational Medicine, Institute of Basic Medical Science, X'ian Medical University, Xi'an, Shaanxi 710021, P.R. China.
authors.forename: Aili
authors.initials: A
authors.lastname: Yan
authors.affiliation: Laboratory of Cell Biology and Translational Medicine, Institute of Basic Medical Science, X'ian Medical University, Xi'an, Shaanxi 710021, P.R. China.
authors.forename: Xingchun
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Cell Biology and Genetics, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Laboratory of Cell Biology and Translational Medicine, Institute of Basic Medical Science, X'ian Medical University, Xi'an, Shaanxi 710021, P.R. China.
authors.forename: Xinying
authors.initials: X
authors.lastname: He
authors.affiliation: Laboratory of Cell Biology and Translational Medicine, Institute of Basic Medical Science, X'ian Medical University, Xi'an, Shaanxi 710021, P.R. China.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Laboratory of Cell Biology and Translational Medicine, Institute of Basic Medical Science, X'ian Medical University, Xi'an, Shaanxi 710021, P.R. China.
authors.forename: Man
authors.initials: M
authors.lastname: Mi
authors.affiliation: Department of Pathology, Sichuan College of Traditional Chinese Medicine, Mianyang, Sichuan 721000, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Tang
authors.affiliation: Laboratory of Cell Biology and Translational Medicine, Institute of Basic Medical Science, X'ian Medical University, Xi'an, Shaanxi 710021, P.R. China.
authors.forename: Xingchun
authors.initials: X
authors.lastname: Gou
mesh_terms: D001599:Berberine / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D001599:Berberine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus