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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we show that N-acetylcysteine (NAC), a precursor of glutathione and an intracellular free radical scavenger, almost completely prevented hepatocyte growth factor (HGF)-suppressed growth of Sarcoma 180 and Meth A cells, and HGF-induced apoptosis, assessed by DNA fragmentation, and increase in caspase-3 activity, in Sarcoma 180 cells. The reduced form of glutathione also prevented HGF-suppressed growth of the cells as effective as NAC. Ascorbic acid partially prevented the effect of HGF, but other antioxidants such as superoxide dismutase, catalase, and vitamin E, and the free radical spin traps N-t-butyl-alpha-phenylnitrone and 3,3,5, 5-tetramethyl-1-pyrroline-1-oxide did not have protective effects. HGF caused morphological changes of the cells, many cells showing condensation and rounding, and enhanced the generation of intracellular reactive oxygen species (ROS) as judged by flow cytometric analysis using 2',7'-dichlorofluorescein diacetate. NAC completely prevented both HGF-induced morphological changes and the enhancement of ROS generation in the cells. However, NAC did not prevent the HGF-induced scattering of Madin-Darby canine kidney cells. To our knowledge, this is the first report that HGF stimulates the production of ROS, and our results suggest the involvement of oxidative stress in the mechanism by which HGF induces growth suppression of tumor cells.
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PMID:Involvement of oxidative stress in tumor cytotoxic activity of hepatocyte growth factor/scatter factor. 1022 23

Epidemiological studies suggest that the consumption of green tea may help prevent cancers in humans, and also breast and prostate cancers in animal models are reduced by green tea, and several mechanisms have been proposed for these effects. In this study the relationship between cellular sulfhydryl (SH) groups and the cytotoxicity of green tea polyphenols in Ehrlich ascites tumor cells was examined. It was found that in the presence of green tea extract (GTE) (100 microg/ml) and one of its polyphenolic components, epigallocatechin (EGC; 100 microM), both cellular non-protein (GSH) and protein-sulfhydryl (PSH) levels were significantly decreased and this was associated with a decrease in cell viability. Replenishing the thiol levels by using N-acetylcysteine (NAC) caused a recovery in cell viability, but this recovery was dependent on the time of thiol replenishment in the presence of EGC (initial 15 min). These results identify SH groups as a novel target of green tea polyphenols cytotoxicity in tumor cells, and a regulatory role for green tea in terms of reducing sulfhydryls in tumor inhibition.
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PMID:Cellular thiols status and cell death in the effect of green tea polyphenols in Ehrlich ascites tumor cells. 1047 15

The incidence of skin cancer is increasing rapidly, particularly in the Caucasian population. Epidemiological and experimental studies demonstrated that ultraviolet radiation (UVR) is the primary cause for the increasing incidence of skin cancer. It is well known that UV irradiation induces DNA damage. If the damage is not repaired or removed in time, it can lead to mutations and skin carcinogenesis. N-acetylcysteine (NAC) has been shown to be an effective protector against UVB-induced immunosuppression and to modulate the expression of some oncogenes and tumor suppressor genes. To test further the protective effect of NAC against UVR, we used both in vitro and in vivo models to investigate the effect of NAC on UVB-induced apoptosis and repair of DNA damage in human and mouse keratinocytes. Our data indicate that the intracellular glutathione level was increased after treatment with NAC at 10-20 mM but decreased with 40 mM NAC treatment due to the toxicity. At concentrations up to 20 mM NAC did not have a significant effect on UVB-induced apoptosis of cultured human keratinocytes. In addition, in an in vivo mouse model, topical application of NAC (3 mumol cm-2) that has been shown to inhibit UVB-induced immunosuppression did not have any effect on UVB-induced apoptosis and did not reduce the formation or enhance the repair of UVB-induced cyclobutane pyrimidine dimers and (6-4) photoproducts. Our results indicate that NAC is ineffective in preserving the genomic stability of keratinocytes against UVB irradiation.
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PMID:Effect of N-acetylcysteine on UVB-induced apoptosis and DNA repair in human and mouse keratinocytes. 1048 60

The thiol N-acetylcysteine (NAC) is a chemopreventive agent that acts through a variety of mechanisms and can prevent in vivo carcinogenesis. We have previously shown that NAC inhibits invasion and metastasis of malignant cells as well as tumor take. Neovascularization is critical for tumor mass expansion and metastasis formation. We investigated whether a target of the anti-cancer activity of NAC could be the inhibition of the tumor angiogenesis-associated phenotype in vitro and in vivo using the potent angiogenic mixture of Kaposi's sarcoma cell products as a stimulus. Two endothelial (EAhy926 and human umbilical vein endothelial [HUVE]) cell lines were utilized in a panel of assays to test NAC ability in inhibiting chemotaxis, invasion, and gelatinolytic activity in vitro. NAC treatment of EAhy926 and HUVE cells in vitro dose-dependently reduced their ability to invade a reconstituted basement membrane, an indicator of endothelial cell activation. Invasion of HUVE cells was inhibited with an ID50 of 0.24 mM NAC, whereas inhibition of chemotaxis required a 10 fold higher doses, indicating that invasion is a preferential target. NAC inhibited the enzymatic activity and conversion to active forms of the gelatinase produced by endothelial cells. The matrigel in vivo assay was used for the evaluation of angiogenesis; NAC strongly inhibited neovascularization of the matrigel sponges in response to Kaposi's sarcoma cell products. NAC prevented angiogenesis while preserving endothelial cells, implying that it could be safely used as an anti-angiogenic treatment.
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PMID:N-acetylcysteine inhibits endothelial cell invasion and angiogenesis. 1049 34

The aim of the present work is to study the change with aging in the effect in vitro of several antioxidants: thiazolidine-4-carboxylic acid or thioproline, N-acetylcysteine (NAC), ascorbic acid (AA), and alpha-tocopherol (vitamin E, VE) on the natural killer (NK) activity in mononuclear cells from axillary nodes, spleen, thymus and peritoneal leukocytes from BALB/c male mice. Young (8+/-2 weeks), adult (24+/-2 weeks). mature (48+/-2 weeks), and old (72+/-2 weeks) animals were studied. A nonradioactive cytotoxic assay with cells from the murine lymphoma YAC-1 as target cells and a relation effector cells/target cells of 10/1 were used. The concentrations of the different antioxidants were: 1 mM for thioproline and N-acetylcysteine and 5 microM for ascorbic acid and alpha-tocopherol, which induced a maximum effect in our previous dose-response experiments. The results show that, in general, the above antioxidants cause an enhancement of the NK activity at all ages studied, this stimulation being higher with thioproline and N-acetylcysteine than with ascorbic acid and alpha-tocopherol. The effects were similar for the three lymphoid organs and the peritoneum. This stimulation of the NK activity by antioxidants is an important favorable response, especially in old mice, in which age results in a decrease in NK function and, therefore, in a higher incidence of neoplasia.
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PMID:Effects in vitro of several antioxidants on the natural killer function of aging mice. 1053 Jul 92

We have shown that the loss of p53 function contributed to resistance of tumor cells to TNF-induced cytotoxicity. In the present study, we evaluated the effect of wild-type p53 (wt-p53) expression on TNF sensitivity, by introducing wt-p53 into MCF7/Adr cells in which p53 was deleted, via a recombinant adenovirus encoding p53 (Ad-p53). Our results indicate that infection with Ad-p53 (50-100 viral particles per cell) resulted in pronounced cytotoxicity, whereas infection with 10 viral particles per cell, which was weakly toxic for the MCF7/Adr cells, sensitized these cells to TNF-induced cell death. Moreover, expression of wt-p53 in MCF7/Adr cells induced the production of reactive oxygen intermediates (ROIs) and caused glutathione (GSH) depletion, indicating disturbances in the cellular redox state. Additional treatment of cells with the anti-oxidant and glutathione (GSH) precursor N-acetylcysteine (NAC) resulted in inhibition of p53-induced ROIs production and in partial restoration of intracellular GSH levels, which was associated with the ability of NAC to inhibit p53-modulated TNF-induced cytotoxicity. Interestingly, Ad-p53 was able to inhibit TNF-induced MnSOD mRNA expression in MCF7/Adr cells, which might contribute to the sensitization of cells to the cytotoxic action of TNF. Taken together, our data strongly suggest that wt-p53 expression sensitizes TNF-resistant MCF7 cells with p53 deletion to TNF-induced cell death by a pathway that is dependent on ROIs production.
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PMID:Adenovirus-mediated wild-type-p53-gene expression sensitizes TNF-resistant tumor cells to TNF-induced cytotoxicity by altering the cellular redox state. 1058 90

Selective induction of cell death is a means to remove unwanted cell populations from a tissue or organ. Understanding the signaling events responsible for mediating cell death by cytokines, such as tumor necrosis factor-alpha (TNFalpha) are key to the development of pharmacologic inducers of this response. Ceramide has been implicated as a secondary messenger for TNFalpha-induced cell death, but many of the intracellular effects of ceramide are not fully understood. Recent reports suggest that ceramide signaling may involve oxidative stress. To explore the relationship between TNF sensitivity and ceramide signaling, two genetic variants of mouse JB6 RT101 epidermal tumor cells, one resistant and one sensitive to TNFalpha-induced cytotoxicity, were treated with C2-ceramide. Treatment with 20 microM ceramide induced apoptosis and this was quickly followed by oncotic necrosis in the TNFalpha-sensitive JB6 (TNFs) cells. The same concentration of ceramide induced apoptosis, but not oncotic necrosis of the TNFalpha resistant JB6 (TNFr) cells. The basal level of glutathione was significantly higher in TNFr cells than in TNFs cells. Treatment with 20 microM ceramide decreased cellular glutathione in TNFs cells by 50%, in contrast to an insignificant decrease in the TNFr cells. A significant increase in reactive oxygen was noted in TNFs cells treated with 10 or 20 microM ceramide. Furthermore, pretreatment with the antioxidant N-acetylcysteine or with glutathione monoethylester delayed the onset of ceramide-induced oncotic necrosis, but did not inhibit apoptosis. Our results suggest that the severity of the decrease in glutathione appears to determine whether cells undergo just apoptosis or also oncotic necrosis. They also suggest that ceramide-induced oncotic necrosis is modulated by a decline in cellular glutathione and an elevation of reactive oxygen. These results suggest that a decrease in cellular redox potential determines susceptibility to ceramide-dependent killing pathways.
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PMID:Effect of ceramide on intracellular glutathione determines apoptotic or necrotic cell death of JB6 tumor cells. 1065 20

Lung cancer is the leading cause of cancer death in the United States. The persisting grim lung cancer incidence and mortality figures argue powerfully for new approaches such as chemoprevention for controlling this disease. Retinoids are among the most intensively studied cancer chemoprevention agents, including in the lung. Several randomized clinical or translational chemoprevention trials (e.g., of retinoids, beta-carotene, or combined folic acid and vitamin B(12)) have been conducted in lung pre-malignancy. Retinoid studies have produced important data on molecular/cellular markers of lung carcinogenesis, e.g., loss of heterozygosity (LOH) at 3p and 9p and retinoic acid receptor-beta (RAR-beta). Two large randomized trials with a lung cancer endpoint, the Alpha-Tocopherol, Beta-Carotene (ATBC) Prevention Study and the Beta-Carotene and Retinol Efficacy Trial (CARET), found that beta-carotene (+/- retinol) was harmful (in smokers). Recently completed lung-second-primary-tumor-prevention trials include the retinoids retinyl palmitate and 13-cis-retinoic acid (13cRA) and N-acetylcysteine (NAC). Vitamin E and selenium show promise for lung cancer prevention, based on positive secondary/subset analyses of three large-scale, randomized National Cancer Institute (NCI) cancer prevention trials. Future directions of lung cancer chemoprevention include the study of molecular markers of risk and drug activity, molecular targeting study, improved imaging techniques (e.g., molecular imaging) and new drug delivery systems.
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PMID:Lung cancer chemoprevention. 1065 11

We have extensively studied the effects of N-acetylcysteine (NAC), a cytoprotective drug that can prevent in vivo carcinogenesis. Here we review our findings NAC completely inhibits gelatinolytic activity of metalloproteases and chemotactic and invasive activities of tumor cells. In addition, NAC reduces the number of lung metastases when malignant murine melanoma cells are injected into nude mice. NAC treatment decreases the weight of primary tumors and produces a dose-related increase in tumor latency. Moreover, oral administration of NAC reduces the formation of spontaneous metastases. In experimental metastasis assays, we have found a synergistic reduction in the number of lung metastases after treatment with doxorubicin (DOX) and NAC in nude mice. In tumorigenicity and spontaneous metastasis assays, the combined administration of DOX and oral NAC again has shown synergistic effects on the frequency and weight of primary tumors and local recurrences and completely prevented the formation of lung metastases. The addition of NAC to endothelial cells strongly reduces their invasive activity in response to angiogenic stimuli. NAC inhibited the degradation and release of radiolabeled type IV collagen by activated endothelial cells, indicating that NAC blocks gelatinase activity. Oral administration of NAC reduces the angiogenic response induced by KS tumor cell products, confirming the ability of NAC to inhibit the invasive activity of endothelial cells in vivo and thereby blocking angiogenesis.
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PMID:The role of the thiol N-acetylcysteine in the prevention of tumor invasion and angiogenesis. 1066 58

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin), the prototype agonist of the aromatic hydrocarbon (Ah) receptor, is a potent tumor promoter as well as a complete liver carcinogen that produces an oxidative stress response in rodents and in cultured cell lines. It has been proposed that TCDD promotes neoplastic transformation through oxidative signal transduction pathways, which results in activation of immediate-early response transcription factors. To set the stage for a test of this hypothesis, we evaluated the effect of TCDD treatment on the activation of several transcription factors, including those in the nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) families, which are activated by changes in the redox state of cells. In an extension of prior results, we found that TCDD treatment produced a sustained overexpression of AP-1 for at least 72 hr in wild-type mouse hepatoma Hepa-1 cells, but not in the Ah receptor-deficient derivative c35 or in cytochrome P450-1A1 (CYP1A1)-negative c37 cells. In addition, TCDD treatment caused a significant increase in the DNA binding activity of NF-kappaB, but not in the activities of the other transcription factors tested. AP-1 and NF-kappaB activation were blocked by the thiol antioxidant N-acetylcysteine and by nordihydroguaiaretic acid, an antioxidant and lipooxygenase inhibitor and an inhibitor of the epoxygenase activity of CYP1A1, and did not take place in c35, c37, or in Ah nuclear translator-deficient c4 cells. Hence, sustained activation of these two transcription factors by TCDD is likely to result from a CYP1A1-dependent and Ah receptor complex-dependent oxidative signal. Electrophoretic mobility supershift analyses with specific antibodies showed that most of the increase in NF-kappaB binding activity could be accounted for by increases in p50/p50 complexes. Since these complexes are known to repress NF-kappaB-dependent gene transcription, our results delineate a second molecular mechanism, in addition to the recently found block of tumor necrosis factor-alpha-mediated p50/p65 activation, that may be responsible for the immunosuppresive effects of TCDD.
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PMID:Activation of transcription factors activator protein-1 and nuclear factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. 1069 65


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