title: Swainsonine inhibits growth and potentiates the cytotoxic effect of             paclitaxel in hepatocellular carcinoma in vitro and in vivo.
abstract: Swainsonine, an extract from Astragalus membranaceus, exhibits broad inhibition             of growth and pro-apoptotic activity in a number of tumor types. However, the             underlying mechanism involved remains unclear. To investigate the effects and             mechanisms of swainsonine on hepatocellular carcinoma (HCC), we performed experiments             on HepG2, SMCC7721, Huh7 and MHCC97-H human hepatoma and HL-7702 human hepatocyte             cells. We observed that swainsonine significantly inhibited the viability of human             hepatoma cells in a dose- and time-dependent manner, but did not affect human             hepatocytes. Due to their highly proliferative and tumorigenic nature, we selected             MHCC97-H cells as a model system to examine. Swainsonine significantly inhibited             MHCC97-H cell growth by causing cell cycle arrest at the G0/G1 phase and the induction             of apoptosis. Blockage of G0/G1 phase was accompanied by a decrease in cyclins             (D1 and E) and cyclin-dependent kinases (Cdk2 and Cdk4) and an increase in the             Cdk inhibitors p21 and p27. Furthermore, swainsonine enhanced the apoptosis of             MHCC97-H cells with the induction of the upregulation of Bax and the downregulation             of Bcl-2, whereas the expressionof Fas and Fas-L remained almost unchanged. These             changes were accompanied by the enhanced cytoplasmic accumulation of nuclear factor             κB (NF-κB) with a concomitant decrease in the nuclear fraction. Importantly, swainsonine             also potentiated the cytotoxic effects of paclitaxel in vitro and in vivo, in             part, by restricting the paclitaxel-induced nuclear accumulation of NF-κB. Taken             together, these results suggest that swainsonine may be an important agent against             HCC via directly inhibiting HCC cell growth and enhancing the responsiveness of             HCC cells to paclitaxel.
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: You
authors.forename: Weihui
authors.initials: W
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Ru
authors.initials: R
authors.lastname: Ji
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.forename: Zhenbing
authors.initials: Z
authors.lastname: Gong
authors.forename: Kefeng
authors.initials: K
authors.lastname: Dou
authors.forename: Kaishan
authors.initials: K
authors.lastname: Tao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D027885:Astragalus propinquus; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000096:biosynthesis; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D004357:Drug Synergism; D053222:Fas Ligand Protein / Q000096:biosynthesis; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016328:NF-kappa B / Q000096:biosynthesis; D017239:Paclitaxel / Q000494:pharmacology*; D017026:Swainsonine / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016328:NF-kappa B; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D017239:Paclitaxel; D017026:Swainsonine