Swainsonine inhibits growth and potentiates the cytotoxic effect of paclitaxel in hepatocellular carcinoma in vitro and in vivo

Abstract

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.

Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells

“…24 We previously found CD133 and EpCAM are useful markers for Huh-7 subpopulations, and the CD133 − /EpCAM − Huh-7 subpopulation possesses a profound invasive ability comparing with their DP counterparts. 17 In the supplementary data, we showed that three highly metastatic hepatoma cell lines, SMCC-7721, MHCC-97H and MHCC-97L, from the Shanghai region, 5,25 were all CD133-negative and EpCAM-negative by flow cytometric analysis (supplementary Figure 1). These DN hepatoma cell lines express high levels of Gli2 and MMP-1/2 (60-155-fold increase) compared with unsorted Huh-7 cells (supplementary Figure 2).…”

Compound Astragalus and Salvia miltiorrhiza extracts suppress hepatocarcinogenesis by modulating transforming growth factor‐β/Smad signaling

“…Astragalus membranaceus (AM) and Salvia miltiorrhiza (SM), commonly used Chinese medicinal plants, have been shown to be effective in suppressing hepatocarcinogenesis in rats and in human, [1][2][3][4][5][6][7][8][9][10][11][12][13][14] but the mechanism is unclear. Transforming growth factor-β (TGF-β), especially the TGF-β1 isoform, is known to be the critical profibrotic cytokine involved in hepatocellular carcinoma (HCC) development.…”

Fyn arrests swainsonine-induced apoptosis in 293T cells via Akt and its phosphorylation

“…Previous studies have shown that SW enhances apoptosis in MHCC97-H cells, colorectal cancer cells, and human diffuse large B cell lymphoma (Suzuki and Abe, 2008;deFreitas-Junior et al, 2012;You et al, 2012). By upregulating Bax and downregulating Bcl-2, SW promotes apoptosis through activation of the mitochondrial pathway (Li et al, 2012b).…”