ABSTRACT
Newcastle disease virus (NDV) is a potential antitumor agent, and its antitumor effect has been evaluated in preclinical tests. However, the mechanisms of NDV-based antitumor therapy are still not completely clear. In the present study we found that NDV-stimulation enhanced the killing ability of mouse spleen natural killer (NK) cells towards mouse hepatoma cell lines, and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) plays an important role in this tumoricidal activity. NDV stimulation induced up-regulation of TRAIL both at the mRNA and protein levels in NK cells. Blocking TRAIL by antibody (Ab) almost completely eliminated the killing effect of NK cells on hepatoma cell lines. Furthermore, neutralizing interferon (IFN)-γ by Ab could inhibit TRAIL expression and tumoricidal activity of NDV-stimulated NK cells. These results indicated a substantial role of TRAIL as an effector molecule in NDV-induced NK cells mediated tumoricidal activity. The NDV stimulation triggered TRAIL expression in mouse spleen NK cells could be mediated by IFN-γ induction.
Subject(s)
Carcinoma, Hepatocellular/prevention & control , Cytotoxicity, Immunologic/immunology , Killer Cells, Natural/immunology , Liver Neoplasms/prevention & control , Newcastle disease virus/immunology , TNF-Related Apoptosis-Inducing Ligand/metabolism , Virus Replication/immunology , Animals , Antibodies, Monoclonal/pharmacology , Blotting, Western , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/virology , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Humans , In Vitro Techniques , Interferon-gamma/metabolism , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Liver Neoplasms/immunology , Liver Neoplasms/virology , Mice , Mice, Inbred BALB C , Newcastle disease virus/genetics , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Spleen/drug effects , Spleen/immunology , Spleen/metabolism , TNF-Related Apoptosis-Inducing Ligand/antagonists & inhibitors , TNF-Related Apoptosis-Inducing Ligand/immunology , Tumor Cells, CulturedABSTRACT
OBJECTIVE: To study the anti-tumor effects of Newcastle disease virus (NDV) strain D817 on human colon carcinoma model in nude mice. METHODS: The nude mouse model of human colon carcinoma was established by subcutaneous inoculation of human colon cancer LOVO cells. The tumor-bearing mice were given PBS, 5-Fu, high-dose NDV D817, moderate-dose NDV D817 or low-dose NDV D817 via caudal vein injection. The tumor size and weight of mice were measured. The liver damages were examined by histopathology. Apoptosis and necrosis of tumor cells were detected by flow cytometry. The endotumoral content of TNF-alpha was detected using a mouse TNF-alpha ELISA kit. The live virus was detected by hemagglutination (HA) test. RESULTS: The moderate-dose NDV D817 inhibited the tumor growth more apparently than 5-Fu. The tumor growth inhibition rate reached to 48.1%. The liver damage and the weight change caused by NDV were less severe. NDV D817 made an increased apoptosis index and induced production of TNF-alpha. Live virus was not detected in important organs except in the tumor of nude mice by HA test. CONCLUSION: In the anti-tumor process in nude mice bearing xenografts of human colon carcinoma, a suitable dose of NDV D817 is more safe and effective.
