Nitric Oxide Synthase Type III Overexpression By Gene Therapy Exerts Antitumoral Activity In Mouse Hepatocellular Carcinoma

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• 作者：Raú ; l Gonzá ; lez^a ; Á ; ngel J. De la Rosa^b ; ¹ ; Santiago Romero-Brufau^c ; Lydia Barrera-Pulido^d ; Francisco Gallardo-Chamizo^b ; Sheila Pereira^b ; Luí ; s M. Marí ; n^d ; José ; M. Á ; lamo^d ; ¹ ; Á ; ngeles Rodrí ; guez-Herná ; ndez^b ; Francisco J. Padillo^d ; ¹ ; Jordi Muntané ; ^d ; ¹
• 刊名：Redox Biology
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：5
• 期：Complete
• 页码：420-421
• 全文大小：64 K

文摘

Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO) synthase type III (NOS-3) overexpression induces cell death in hepatoma cells. The study developed gene therapy designed to specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. Hepa 1-6 cells were used for in vitro and in vivo experiments. The first generation adenovirus was designed to overexpress NOS-3 (or GFP) and luciferase cDNA under the regulation of murine alpha-fetoprotein (AFP) and Rous Sarcoma Virus (RSV) promoters, respectively. Both adenoviruses were administered through the tail vein two weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-Luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8 activity in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by l-NAME or p53 siRNA. The tail vein infusion of AFP-NOS- 3/RSV-Luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.