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Mar Drugs
2014 Jul 24;128:4274-90. doi: 10.3390/md12084274.
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Cytotoxic and apoptosis-inducing activity of triterpene glycosides from Holothuria scabra and Cucumaria frondosa against HepG2 cells.
Wang J
,
Han H
,
Chen X
,
Yi Y
,
Sun H
.
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The cytotoxic effects of thirteen triterpene glycosides from Holothuria scabra Jaeger and Cucumaria frondosa Gunnerus (Holothuroidea) against four human cell lines were detected and their cytotoxicity-structure relationships were established. The apoptosis-inducing activity of a more potent glycoside echinoside A (1) in HepG2 cells was further investigated by determining its effect on the morphology, mitochondrial transmembrane potential (Δψm) and mRNA expression levels of the apoptosis-related genes. The results showed that the number of glycosyl residues in sugar chains and the side chain of aglycone could affect their cytotoxicity towards tumor cells and selective cytotoxicity. 1 significantly inhibited cell viability and induced apoptosis in HepG2 cells. 1 also markedly decreased the Δψm and Bcl-2/Bax mRNA express ratio, and up-regulated the mRNA expression levels of Caspase-3, Caspase-8 and Caspase-9 in HepG2 cells. Therefore, 1 induced apoptosis in HepG2 cells through both intrinsic and extrinsic pathway. These findings could potentially promote the usage of these glycosides as leading compounds for developing new antitumor drugs.
Figure 1. Chemical structures of triterpene glycosides 1–13 from H. scabra and C. frondosa. Glc: β-d-glucopyranosyl; MeGlc: 3-O-methyl-β-d-glucopyranosyl; Qui: β-d-quinovo-pyranosyl; Xyl: β-d-xylopyranosyl; S1: Qui-(1→2)-4-O-SO3Na-Xyl-; S2: MeGlc-(1→3)-Glc-(1→4)-Qui-(1→2)-4-O-SO3Na-Xyl-; S3: MeGlc-(1→3)-Xyl-(1→4)-Qui-(1→2)-4-O-SO3Na-Xyl-; S4: MeGlc-(1→3)-Xyl-(1→4)-[Xyl-(1→2)]-Qui-(1→2)-4-O-SO3Na-Xyl-; S5: MeGlc-(1→3)-Xyl-(1→4)-[Xyl-(1→2)]-Qui-(1→2)-4-O-SO3H-Xyl-; (a) and (b): Aglycone; (c–i): R2.
Figure 2. Effect of 1 on cell viability of HepG2 cells. HepG2 cells were treated with the various concentrations of 1 for 6 and 12 h, and cell viability was measured using the MTT assay. The values are presented as means ± SD (n = 5).
Figure 3. Morphological changes of HepG2 cells after treatment with 1 for 8 h. (a) Morphological changes visualized under a fluorescence microscope after acridine orange (OA) staining; (b) Morphological changes visualized under a fluorescence microscope after Hoechst 33342 staining. The figures shown are representative of three independent experiments.
Figure 4. Mitochondrial transmembrane potential changes of 1-treated HepG2 cells stained with JC-1 at the concentrations of 0 μg/mL (a); 2.5 μg/mL (b); 2.75 μg/mL (c) and 3.0 μg/mL (d). The figures shown are representative of three independent experiments.
Figure 5. Effect of 1 on the ratio of expression level between Bcl-2 and Bax mRNA in HepG2 cells. HepG2 cells were incubated with 1 at the various concentrations for the different time. The mRNA expression levels of β-actin, Bcl-2, and Bax were detected by RT-PCR using specific primers. The values are presented as means ± SD (n = 3). Significant differences with the untreated control group were designated as * p < 0.05, ** p < 0.01 and *** p < 0.001.
Figure 6. Effects of 1 on the mRNA expression level of Caspase-3, Caspase-8 and Caspase-9 in HepG2 cells. HepG2 cells were incubated with 1 at the various concentrations for the different time. The mRNA expression levels of β-actin, Caspase-3, Caspase-8 and Caspase-9 were detected by RT-PCR using specific primers. (a) The mRNA expression of Caspase-3 in HepG2 cells; (b) The mRNA expression of Caspase-8 and Caspase-9 in HepG2 cells. The values are presented as means ± SD (n = 3). Significant differences with the untreated control group were designated as * p < 0.05, ** p < 0.01 and *** p < 0.001.
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