L-NAME inhibits tumor cell progression and pulmonary metastasis of r/m HM-SFME-1 cells by decreasing NO from tumor cells and TNF-alpha from macrophages.
Highly metastatic ras/myc-transformed serum-free mouse embryo (r/m HM-SFME-1) cells were injected subcutaneously to mice and the effects of Nomega-nitro-L-arginine methyl ester (L-NAME) on the tumor progression and pulmonary metastasis were investigated. In addition, production of nitric oxide (NO), matrix metalloproteinases (MMPs) and tumor necrosis factor-alpha (TNF-alpha) in the tumor cells and in a mouse macrophage-like cell line, J774.1 cells, was analyzed. The increase in footpad thickness was significantly smaller in the mice which were fed the L-NAME containing water (4.24+/-0.39 mg/day/mouse). The number of the tumor cells metastasized to the lungs was smaller in the L-NAME treated mice, although statistical significance was not found. Co-treatment of r/m HM-SFME-1 cells with interferon-gamma (IFN-gamma; 100 U/ml) and lipopolysaccharide (LPS; 0.5 microg/ml) significantly enhanced NO production, and the presence of L-NAME at 1 mM significantly decreased this response. In r/m HM-SFME-1 cells, MMP-2 was undetectable and MMP-9 was also very little in the basal level, and both MMPs were unaffected by the IFN-gamma and/or LPS treatments, not to mention by the L-NAME treatment. In J774.1 cells, any treatment including LPS appeared to enhance MMP-9 production, however, this upregulation was not inhibited by the additional presence of L-NAME. Production of TNF-alpha by J774.1 cells was markedly enhanced with LPS treatment, and this enhancement was significantly reduced in the presence of L-NAME. These results indicate that the inhibitory effects of L-NAME on the tumor cell progression and pulmonary metastasis could be due to suppression of NO from tumor cells and TNF-alpha from macrophages (Mol Cell Biochem, 2007).
Yamaguchi
Hideaki
H
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Aomori University, 2-3-1 Kobata, Aomori 030-0943, Japan. yamaguch@aomori-u.ac.jp
Kidachi
Yumi
Y
Umetsu
Hironori
H
Ryoyama
Kazuo
K
D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D018450:Disease Progression; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D016259:Genes, myc; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control* / Q000556:secondary*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology* / Q000627:therapeutic use; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D016283:Proto-Oncogene Proteins p21(ras); D019331:NG-Nitroarginine Methyl Ester