cyclamin and Liver-Neoplasms

In this study, a diverse set of triterpenoid saponins was evaluated to assess their chemosensitizing activity in two human liver cancer cells (Bel-7402 and HepG2) and non-neoplastic HL-7702 liver cells. Cyclamin, a 13,28-epoxy oleanane-type triterpenoid saponin from Ardisia japonica, was identified as a potent chemosensitizer. A low cytotoxic level of cyclamin synergistically enhances the growth inhibitory effect of 5-fluorouracil (from 41.3 ± 1.1% to 64.5 ± 2.3%), cisplatin (from 57.1 ± 1.5% to 79.6 ± 2.7%), and epirubicin (from 62.6 ± 1.2% to 74.9 ± 1.8%) on Bel-7402 cells, but not HL-7702 cells. Flow cytometric analysis shows that cyclamin synergistically enhances the apoptosis and cell cycle arrest induction effects of 5-fluorouracil by 69.4% and 22.2%, respectively. The mechanism of action could be through the activation of caspase-3, -8, and -9, the upregulation of cyclin-dependent kinase 2, the cell division cycle 25 homolog A expression level, or the Bax/B-cell lymphoma 2 ratio. Furthermore, a lactate dehydrogenase release assay demonstrated that cyclamin markedly increases the membrane permeability of Bel-7402 cells, which may also contribute to the mechanism of the chemosensitizing activity of cyclamin. These findings indicate the potential usefulness of cyclamin for the chemoprevention and treatment of liver cancer.

Topics: Antineoplastic Agents; Ardisia; Caspases; Drug Synergism; Hep G2 Cells; Humans; Liver; Liver Neoplasms; Saponins; Triterpenes

Twenty 13,28-epoxy and related triterpenoid saponins from Ardisia japonica were evaluated for their anti-proliferative activity on human liver cancer cells and normal liver cells. Eight saponins selectively inhibited the growth of liver cancer Bel-7402 and HepG-2 cells without affecting the survival of normal liver HL-7702 cells. The structure-activity relationship analyses indicated that the 13,28-epoxy, 16α-hydroxy, and C-30 methyl moieties in the sapogenin parts and the glycosyl moiety consisting from tetra- to hepta-saccharide units are important for this activity. Among the active saponins, ardisianoside B (2) and 3β-O-β-d-glucopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→2)-β-d-glucopyranosyl-(1→4)]-α-l-arabinopyranosyl-13β,28-epoxy-16α-hydroxyoleanane (3) showed the most potent anti-proliferative activity against Bel-7402 cells in a dose- and time-dependent manner. The selective anti-proliferative activity is attributed to the different cellular responses (CDKs and cyclins levels, cell cycle arrest and apoptosis) between tumor and normal liver cells. Exposure to 2 and 3 selectively led to cell cycle arrest and apoptosis in Bel-7402 cells together with the increased pro-apoptotic caspase-8 and the decreased anti-apoptotic Cdc25A levels.

Topics: Antineoplastic Agents, Phytogenic; Ardisia; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Liver Neoplasms; Molecular Conformation; Saponins; Structure-Activity Relationship; Triterpenes