Role in Nitric Oxide in Kupffer Cell-Mediated Hepatoma Cell Cytotoxicity In Vitro And Ex Vivo

Abstract

Kupffer cells account for a major portion of the tissue macThe metabolic changes in tumor cells (AH70, a rat heprophages in the body 1 and play an important role in the deatoma cell line) cocultured with isolated rat Kupffer fense mechanisms of the body. Kupffer cells are ordinarily cells were visualized and analyzed by a laser scanning found in liver sinusoids and, in particular, are located preconfocal imaging system. When AH70 cells were coculdominantly in the area adjacent to the terminal portal tured with Kupffer cells, fluorescence intensity of rhodabranches or in the periportal region. They are first exposed mine 123 (Rh123) decreased, indicating the reduction to harmful substances flowing into the liver through the porof mitochondrial function. The reduction in Rh123 was tal vein, such as endotoxins and viruses, and contribute to eliminated by N G -monomethyl-L-arginine (L-NMMA), an the removal of tumor cells migrating in the liver. 2 analogue of L-arginine, suggesting the involvement of By virtue of the availability of techniques to isolate and nitric oxide (NO). Two hours after the cells were coculculture pure Kupffer cells, a significant progress has been tured, membrane compromised AH70 cells which were achieved in studies on functions and origins of these cells. 3,4 observed as propidium iodide (PI)-positive cells, in-There have been various reports that describe antitumor accreased in number approximately from 2.8% to 25%. This tivities of Kupffer cells. 5-9 However, there are certain points increase was also attenuated by L-NMMA, suggesting remaining to be elucidated with regard to the mechanism that Kupffer cell-mediated injury of tumor cells largely whereby Kupffer cells display antitumor activities. Although depends on NO. The concentration of NO 0 2 / NO 0 3 in the some investigators described that Kupffer cells do not show culture medium markedly increased after coculture of any antitumor activities unless stimulated by cytokines and AH70 cells with Kupffer cells. Moreover, NO synthase endotoxin, 5 we have recently reported that the resting rat (NOS) activity in Kupffer cells significantly increased Kupffer cells have antitumor activities against syngeneic after coculture. These in vitro results suggest that NO hepatoma cells as well as colon cancer cells. 7-9 mediates Kupffer cell-induced tumor cell damage charKupffer cells synthesize and release a variety of immunoacterized by reduced mitochondrial function and dimin-modulating and inflammatory mediators such as oxygen-deished barrier function. In the ex vivo study of the per-rived free radicals, nitric oxide (NO), lipid mediators, and fused liver to which AH70 cells were injected via the cytokines. It is known that NO is a molecule with extremely catheter inserted into the portal vein, some AH70 cells high reactivity that is released in the presence of oxygen, were arrested in the upper stream of sinusoid and the nicotinamide adenine dinucleotide phosphate, and other cofluorescence intensity of Rh123 in adherent AH70 cells enzymes during t...

Staphylococcal entertotoxins of the enterotoxin Gene cluster (egcSEs) induce nitrous oxide- and cytokine dependent tumor cell apoptosis in a broad panel of human tumor cells

“…Selective genetic or pharmacological inhibition of eNOS or iNOS or enzymatic induction of NO deficiency in tumor cells diminishes VEGF, HO-1, and HIF1α activation and consequent tumor cell proliferation and angiogenesis (Kimura et al, 2000; Motterlini et al, 2000; Naughton et al, 2002; Kasuno, 2004). Local release of NO in endothelial cells, liver sinusoids, or pulmonary circulation causes apoptosis of the disseminated tumor cells at these sites (Fukumura et al, 1996; Wang et al, 2000, 2007; Qiu et al, 2003; Qi et al, 2004). Finally, daily intraperitoneal injections of NO-producing nitrovasodilators isosorbide mono-and dinitrate resulted in a significant decrease of the size of the primary tumor and a reduction in the number and size of spontaneous lung metastases (Pipili-Synetos et al, 1995).…”

The dual role of iNOS in cancer

“…High concentrations of NO, more than 500 nM, may be pro-apoptotic, producing cytotoxicity and antitumor activity [33] , [39] . High NO levels that produced cytotoxic effects on tumor cells are derived from macrophages, neutrophils, endothelial cells, hepatocytes, cardiac myocytes and chondrocytes [40] , [41] , [42] , [43] .…”

Tumor Cytotoxicity by Endothelial Cells

“…Meanwhile, our present results indicate that approaches capable of maintaining low mtGSH levels in invasive cells may be important to challenge their survival during macrophage attack or when cancer therapy is applied. Interestingly, it has been shown in hepatoma cells that Kupffer cells have anti-tumor activity through NO-mediated mitochondrial damage to tumor cells (62).…”