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: Nan You, Weihui Liu, Tao Wang, Ru Ji, Xing Wang, Zhenbing Gong, Kefeng Dou, Kaishan Tao
• Journal: Oncology reports (Oncol Rep) Vol. 28 Issue 6 Pg. 2091-100 (Dec 2012) ISSN: 1791-2431 [Electronic] Greece
• PMID: 22993037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyclin E
• Cyclin-Dependent Kinase Inhibitor p21
• FAS protein, human
• FASLG protein, human
• Fas Ligand Protein
• NF-kappa B
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• fas Receptor
• Cyclin D1
• Cyclin-Dependent Kinase Inhibitor p27
• CDK2 protein, human
• CDK4 protein, human
• Cyclin-Dependent Kinase 2
• Cyclin-Dependent Kinase 4
• Paclitaxel
• Swainsonine

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Astragalus propinquus
• Carcinoma, Hepatocellular (drug therapy, pathology, physiopathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin D1 (biosynthesis)
• Cyclin E (biosynthesis)
• Cyclin-Dependent Kinase 2 (biosynthesis)
• Cyclin-Dependent Kinase 4 (biosynthesis)
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis)
• Cyclin-Dependent Kinase Inhibitor p27 (biosynthesis)
• Drug Synergism
• Fas Ligand Protein (biosynthesis)
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, pathology, physiopathology)
• NF-kappa B (biosynthesis)
• Paclitaxel (pharmacology)
• Swainsonine (pharmacology)
• bcl-2 Homologous Antagonist-Killer Protein (biosynthesis)
• bcl-2-Associated X Protein (biosynthesis)
• fas Receptor (biosynthesis)