RESUMEN
P-5m, an octapeptide derived from domain 5 of HKa, was initially found to inhibit the invasion and migration of melanoma cells. The high metastatic potential of melanoma cells was prevented by the HGK motif in the P-5m peptide in vitro and in an experimental lung metastasis model, suggesting that P-5m may play an important role in the regulation of tumor metastasis. The aim of this study was to measure the effect of P-5m on tumor metastasis of human hepatocarcinoma cell line (HCCLM3) in vitro and in vivo in a nude mouse model of hepatocellular carcinoma (HCC), and detect the mechanisms involved in P-5m-induced anti-metastasis. By gelatin zymography, matrix metallo-proteinases 2 (MMP-2) activity in HCCLM3 was dramatically diminished by P-5m peptide. In addition, the migration and metastasis of HCCLM3 cells was also inhibited by the peptide in vitro. In an orthotopic model of HCC in nude mice, P-5m treatment effectively reduced the lung metastasis as well as the expression of MMP-2 in the tumor tissues. Overall, these observations indicate an important role for P-5m peptide in HCC invasion and metastasis, at least partially through modulation MMP-2 expression. These data suggests that P-5m may have therapeutic potential in metastatic human hepatocarcinoma.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Metaloproteinasa 2 de la Matriz/biosíntesis , Oligopéptidos/farmacología , Animales , Productos Biológicos/farmacología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Modelos Animales de Enfermedad , Femenino , Humanos , Quininógeno de Alto Peso Molecular/genética , Quininógeno de Alto Peso Molecular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la NeoplasiaRESUMEN
AIM: To study the cytotoxic effects of doxorubicin on apoptosis in glioma cell lines U343, U138, U373 induced by anti-human DR4/DR5 monoclonal antibodies (FMU1.4/FMU1.5) and the underlying mechanism. METHODS: Expression of DR4/DR5 was quantitated by flow cytometry. Cytotoxicity exerted by FMU1.4/FMU1.5 on three cell lines was measured by MTT colorimetry and the induced apoptosis was determined by agarose gel electrophoresis. The expression of cytochrome C, FLIP and Ca2+ concentration were also measured. RESULTS: Following the treatment of doxorubicin DR4 and DR5 were highly expressed on the cell surface; The apoptosis of U138 and U373 induced by FMU1.4 and FMU1.5 was stronger. expression of cytochrome C and Ca2+ concentration were enhanced, whereas the expression of FLIP was downregulated. CONCLUSION: Subtoxic doxorubicin applied with antibodies caused higher cell death rate of glioma cells, which may be relevant to DR4/DR5, the release of cytochrome C and FLIP and Ca2+ concentration.