The Therapeutic Effect Of Tripeptide Tyroservatide (YSV) On Growth And Metastasis Of Lung Carcinoma And Its Mechanisms

Objective:Metastasis is a very complex biological phenomenon. This study was observed if YSV can inhibit the tumor growth, invasion and metastasis of lung carcinoma and related metastatic mechanisms were approached. Methods:1. Lewis lung cancer spontaneous metastasis models in C57BL/6J mice were established: anti-tumor effect of YSV was observed;anti-metastasis was evaluated by counting metastatic nodules and HE staining.2. The models of human lung carcinoma A549 transplanted into subcutaneous tissues of nude mice were established and the anti-tumor effect of YSV was evaluated. The orthotopic models of human lung carcinoma A549 in nude mice were established and the anti-metastasis effect of YSV was evaluated by counting metastatic nodules and HE staining.3. In vitro, the cell line LLC and A549 was selected to observe the effect of YSV on adhesion and invasion assay.4. Effect of YSV on ICAM-1 mRNA and protein expression in lung metastatic tumor of Experimental Orthotopic Models of Human A549 Lung Carcinoma by Real-time PCR and Western Blot.Results:1. YSV (320μg/kg/d, 160μg/kg/d, or 80μg/kg/d) significantly inhibited the growth of Lewis cells transplanted in mice. The difference of YSV (320μg/kg/d) and the control group is significant (P<0.05) and the tumor growth inhibition rate of YSV (320μg/kg/d) is 30.8%. YSV 320μg/kg/d treatment and the control group is significant (P<0.05) and the metastasis inhibition rate of YSV (320μg/kg/d) is24.52%. HE staining of lung sections of Lewis Lung Carcinoma-bearing C57BL/6J Mice: Treatment with YSV (320|j,g/kg/d) reduced the size and number of tumor cell clusters at metastatic sites and in blood vessels relative to size and number of clusters in the control group.^ 2. YSV (320ug/kg/d, 160ug/kg/d, or 80ug/kg/d) significantly inhibited the growth of A549 cells transplanted in mice. The difference of YSV (320ug/kg/d, 160ug/kg/d, or 80ng/kg/d ) and the control group is significant (PO.05) and the tumor growth inhibition rate of YSV (320ug/kg/d) is 46.97%. YSV significantly inhibited the lung metastasis of A549 cells transplanted in nude mice. The difference of YSV (320ug/kg/d) and the control group is significant (PO.05) and the metastatic inhibition rate of YSV (320 ng/kg/d) is 31.43%. HE staining of lung sections of Human A549 Lung Carcinoma-bearing nude mice: Treatment with YSV (320ug/kg/d) reduced the size and number of tumor cell clusters at metastatic sites and in blood vessels relative to size and number of clusters in the control group.3. The proliferation abilities of LLC cells and A549 cells were inhibited obviously after pretreated with YSV (0. Ol^ig/ml, 0.1p.g/ml, lug/ml, 10^g/ml, lOOug/ml) for 24, 48 and 72hrs. The difference of every YSV treatment group and the control group is significant (PO.05). The number of cells adhering to Matrigel can reflected the adhesive ability of tumor cells. After pretreated with different doses of YSV for 24, 48 and 72hrs, the adhesive ability of A549 cells to Matrigel was inhibited obviously by YSV (0.001 ng/ml, O.Olug/ml, 0.lug/ml, l|xg/ml, lOug/ml). After pretreated with different doses of YSV (O.OOlug/ml, 0.0\[ig/m\, O.lug/ml, l(ag/ml, 10|j.g/ml) for 48h, the invasion of A549 cells was inhibited obviously by YSV. The cells that had migrated to the lower surface of the filter inevery YSV treatment group are less than those in the control group. Thedifference of every YSV treatment group and the control group is significant(PO.05). 4. YSV significantly down-regulated ICAM-lmRNA and protein expression inmetastatic tumor of Experimental Orthotopic Models of Human A549 LungCarcinoma. The difference of YSV treatment group and the control group issignificant (PO.05). Conclusion:YSV had anti-tumor and anti-metastatic effect on Lewis lung carcinoma-bearing C57BL/6J mice and experimental orthotopic models of human A549 lung carcinoma. YSV inhibited the proliferation of LLC and A549. YSV inhibited the adhesion and invasion of A549. YSV down-regulated the expression of ICAM-1 in A549. In conclusion, YSV can effectively inhibit the proliferation, invasion and metastasis of lung carcinoma.