Ginsenoside Rg3 Prolongs Survival of the Orthotopic Hepatocellular Carcinoma Model by Inducing Apoptosis and Inhibiting Angiogenesis

Figures

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  Figure 1. The experiment design and illustration. After implantation with Hep-1 HCC tumor cells (day 0), altogether, 20 HCC tumor-bearing mice were randomly divided into two groups: the control group (n = 10) and the Rg3 treatment group (n = 10). They were fed orally by normal saline (0.2 ml/mouse, once a day) or Rg3 (10 mg/kg) for 30 days (day 1-day 30). The experiment was investigated for three months.

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  Figure 2. The mouse survival by Kaplan-Meier survival analysis. Hep1-6 HCC tumor-bearing mice were treated with normal saline, control (blue curve), or Rg3 (red curve). Survival was based on the length of time after the Hep1-6 HCC tumor volume reached 2 cm3 (time when the animal was euthanized). The median survival for control was 65 days and 86 days for Rg3-treated mice (log-rank test P < 0.05). Kaplan-Meier analysis shows that mice with Rg3 treatment had a significant higher survival rate than the control without Rg3 treatment (P < 0.05).

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  Figure 3. The mouse weight follow-up study. The animal weight in the control and Rg3 groups both increased in the first month after the Hep1-6 tumor cubes were implanted in the liver lobe. After the initial 30 days when the tumor developed, the tumor-bearing mice began to stop gaining weight. Statistical analysis showed that there was no significant difference between the average weights between the two groups, suggesting that the Rg3 had no negative effect on the body weight of the hepatocellular carcinoma-bearing mice.

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  Figure 4. Rg3 inhibit on Hep-1 HCC tumor development in vivo. At the end of the experiment, mice were sacrificed to dissect the tumors. The weight of the tumor from mice was scaled. P < 0.05 vs. the control group, suggesting Rg3 decreased the Hep1-6 HCC tumor growth in mice.

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  Figure 5. The quantities of apoptotic and microvessel density analysis. Apoptotic cells and microvessels were quantified as the average of 10 fields selected per tumor (magnification was shown as the bar). The CD105 is an endothelium marker that was found highly expressed in HCC. The MVD-CD105 positively stained tumor vessels were significantly less in the Rg3 group than in the control group (P < 0.05). In addition, the apoptotic rate increased dramatically in the Rg3 group vs. the control group (P < 0.05).

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  Figure 6. The molecular mechanical illustration. In order to further elucidate the mechanisms of the Rg3 antitumor effects, the orthotopic HCC tumor-bearing mouse was followed up to 3 months with the 30-day oral taking of Rg3 in the early stage of tumor development when the initial tumor was implanted in the liver. Results showed that apoptosis induction and angiogenesis was significantly detected in tumor tissue by Rg3 treatment, contributing to the tumor shrinkage and negative remote metastasis. Rg3 initialized the tumor apoptotic progress, which then weakened the tumor volume and its capability to produce the vascularized network for tumor growth and further metastasis.