| Objective: This study is to observe the inhibitory effects of GinsenosideRg3, an active ingredient of Chinese traditional medicine, in combination withSuramin on the proliferation and metastasis of the Lewis lung cancer (LLC) in mice,and to investigate the possible molecular mechanisms.Methods: Lewis lung cancer cells were inoculated into40C57BL6mice toestablish lung cancer models. The mice were randomly divided into5groups asfollows: control group (n=8), cisplatin group (n=8), Ginsenoside Rg3group (n=8),suramin group (n=8), and Ginsenoside Rg3plus Suramin joint group (n=8). Four daysafter intervention, the mice were administrated according to the following protocol.The control group was treated with normal saline. The cisplatin group wasintraperitoneally injected by3mg/(kg·5d) of cisplatin. The Ginsenoside Rg3groupwas treated with5mg/(kg·d) of Ginsenoside Rg3by gavage. The Suramin group wasintraperitoneally injected by10mg/(kg·d) of Suramin. The Ginsenoside Rg3plusSuramin joint group were treated with5mg/(kg·d) of Ginsenoside Rg3and10mg/(kg·d) of Suramin. During the course of experiment, the general condition of the miceand the adverse reactions of medication were observed, and the mice transplantedtumor growth volume was measured. Sixteen days after the drug intervention, themetastasis nodules on lung surface and the transplantated tumor weight weremeasured among groups. The pathological changes of lung tissue were observed byHE staining. The expression of CD34(MVD) in transplantation tumor was measuredusing immunohistochemical method. The mRNA levels of TGF-β1, MEK1/2andERK1/2were examined through semiquantitative reverse transcription-polymerasechain reaction (RT-PCR). Protein expression of these genes and p-ERK1/2were examined by western blot method.Results:1. Mice transplanted tumor growth and metastasis to the lungs situationThe12-20days after inoculation, the tumor volume growth rate in the treatmentgroups was obviously slower than that in the control group, and the Ginsenoside Rg3plus Suramin joint group was slowest among groups (P<0.05). The weight oftransplantation tumor in the drug intervention groups was decreased as compared withcontrol group. In addition, the joint group was lower than other drug group (P<0.05),control group:(5.60±0.34) g, cisplatin group:(4.50±0.40) g, Ginsenoside Rg3group:(3.60±0.31) g, Suramin group:(3.58±0.27) g, Ginsenoside Rg3plusSuramin joint group:(2.82±0.26) g. The amount of metastasis nodules on lungsurface was similar with the weight of transplantation tumor (P<0.05), control group:7.00±3.02, cisplatin group:4.75±2.12, Ginsenoside Rg3group:3.13±1.25,Suramin group:2.75±1.67, Ginsenoside Rg3plus Suramin joint group:0.75±0.71.The metastasis rate on lung surface was100%,100%,100%,87.5%and62.5%respectively. The tumor inhibitory rate was19.69%,35.37%,35.85%and49.39%,and the metastasis inhibitory rate was32.1%,55.3%,60.75%,89.3%in the cisplatin,Ginsenoside Rg3, Suramin, Ginsenoside Rg3combined with Suramin therapy grouprespectively. The factorial experiment for the Ginsenoside Rg3and Suramin hadinteraction in the tumor inhibitory rate and the metastasis inhibitory rate, and theGinsenoside Rg3had synergistic effect combined with Suramin.2. The expression of MVD in the transplanted tumor of miceThe expression of MVD in the treatment groups were obviously lower than thatin control group, and the Ginsenoside Rg3plus Suramin joint group was lower thanthat in other drug-treated groups (P<0.05). The inhibition effect of angiogenesis in thejoint group was more effective than the individual application, and the expression ofMVD were24.06±2.40,19.41±1.98,13.06±1.92,12.09±1.49and6.16±1.17inthe control, cisplatin, Ginsenoside Rg3, Suramin, Ginsenoside Rg3combined withSuramin therapy group, respectively. 3. The expression of TGF-β1in the transplanted tumor of miceThe expression of TGF-β1in the treatment groups were obviously lower thanthat in control group, and the Ginsenoside Rg3plus Suramin joint group was lowerthan that in other drug-treated group (P<0.05), the TGF-β1highly expressed in thecontrol group without drug intervention. The mRNA of TGF-β1was (86.17±8.28)%,(64.69±6.63)%,(49.37±4.24)%,(46.85±4.56)%,(32.08±3.78)%in thecontrol, cisplatin, Ginsenoside Rg3, Suramin, Ginsenoside Rg3combined withSuramin therapy group, respectively. The protein expression of TGF-β1was (114.68±17.06)%,(86.40±18.46)%,(65.54±20.02)%,(66.72±18.86)%,(45.79±16.06)%in every group, respectively.4. The influence of ERK signaling pathway on the transplanted tumor ofmiceThe Ginsenoside Rg3and Suramin had little effect on the expression of MEK1/2,but these two drugs could inhibit the phosphorylation of ERK1/2. The mRNA andprotein of MEK1/2had no significant difference among groups (P>0.05). Theexpression of ERK1/2mRNA was (71.93±13.47)%,(56.43±11.01)%,(45.27±8.82)%,(43.29±7.48)%and (28.75±5.41)%in the control, cisplatin, GinsenosideRg3, Suramin, Ginsenoside Rg3plus Suramin joint group, respectively. Theexpression of ERK1/2protein was (104.18±9.78)%,(84.61±7.66)%,(76.71±7.25)%,(74.01±7.41)%and (51.69±5.29)%in the control, cisplatin, Ginsenoside Rg3,Suramin, Ginsenoside Rg3plus Suramin joint group respectively. The expression ofp-ERK1/2protein was (112.96±9.49)%,(87.86±6.77)%,(61.26±8.48)%,(38.60±10.66)%and (9.57±3.42)%in the control, cisplatin, Ginsenoside Rg3, Suramin,Ginsenoside Rg3plus Suramin joint group, respectively.5. The correlation of each indicatorsThe expression of MVD, TGF-β1, ERK1/2was negative correlation with thetumor inhibitory rate and positive correlation with the amount of metastasis noduleson lung surface. The expression of TGF-β1, ERK1/2was highly relevant with MVD(P<0.05). Conclusion:1. Ginsenoside Rg3and Suramin may effectively inhibit the growth andmetastasis of Lewis lung cancer in mice, and Suramin combined with GinsenosideRg3inhibited more effectively with synergism, which related to inhibite theangiogenesis via suppressing the activation of ERK Pathway.2. Ginsenoside Rg3and Suramin may inhibit terminal lung cancer of growth andmetastasis effectively, which is involved in the suppression of TGF-β1expression.3. Ginsenoside Rg3and Suramin joint therapeutic method is one of treatment ofcombined Chinese traditional medicine and Western medicine. Compared withcisplation Group, the joint Group has less side effects so that they may play aprotective role in the anti-tumor therapy. |
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