UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular metabolism of chromium(VI) [Cr(VI)] may lead to oxidative stress and this may account for the ability of Cr(VI) to act as a complete carcinogen. Therefore, we examined the effects of Cr(VI) treatment on the expression of oxidative stress genes in normal human lung LL 24 cells and human lung adenocarcinoma A549 cells. RT-PCR and northern blot analyses were used to determine the steady-state mRNA levels of catalase, glutathione S-transferase, glutathione reductase, Cu/Zn- and Mn-superoxide dismutases, glutathione peroxidase, NAD(P)H:quinone oxidoreductase, heme oxygenase and interleukin 8 in control cells and cells treated with 5-200 microM of Cr(VI). We found that only expression of the heme oxygenase gene is strongly elevated under the treatment with Cr(VI), and only in normal human lung LL 24 cells. Our data showed that even in the absence of Cr(VI) treatment, the level of heme oxygenase gene expression is much higher in A549 cells than in LL 24 cells. As glutathione is believed to play a protective role in cells against different forms of oxidative stress, we studied the correlation between intracellular glutathione levels and the inducibility of the heme oxygenase gene after treatment of cells with Cr(VI). Our results demonstrate that glutathione levels are increased by 35 % of control values in LL 24 cells treated with Cr(VI). The data obtained indicate that heme oxygenase, known to be a stress-inducible gene, may be involved in cellular pathways critical to the carcinogenic activity of Cr(VI) in normal human lung cells. Intracellular glutathione levels and reactive oxygen species do not appear to be primarily responsible for the stress response, induced by Cr(VI) in the studied human cells.
Carcinogenesis 1998 Aug
PMID:Effects of Cr(VI) on the expression of the oxidative stress genes in human lung cells. 974 36

Pentachlorobenzene (PeCB) is an important environmental contaminant derived primarily from the by-product contamination of the popular fungicides hexachlorobenzene and pentachloronitrobenzene. Its tumor-promoting activity was studied in a medium-term initiation/promotion assay in male F344 rats. Animals were given a single i.p. injection of diethylnitrosamine (200 mg/kg body weight) and 2 weeks later were administered 0.1 or 0.4 mmol/kg per day PeCB by gavage in a corn oil vehicle, 7 days/week. At the end of week 3, rats were subjected to a partial hepatectomy. Results showed that PeCB, at both doses, significantly increased both the number and area of glutathione S-transferase pi (GST-P) foci (>0.2 mm diameter) (P < 0.05). This trend was dose-dependent. In addition to increases in preneoplastic foci, liver glutathione concentrations and glutathione-associated enzymes showed significant changes in animals treated with PeCB. Glutathione reductase (GR) and gamma-glutamylcysteine synthetase (gamma-GCS) were both significantly induced in the centrilobular region. Changes in oxidized glutathione concentrations corresponded with the increase in GR activity with decreases of 40 and 30% in the low and high dose groups, respectively. No significant changes were detected in reduced glutathione concentrations. Together with changes in GR and gamma-GCS expression, a decrease in GST-P foci around the central veins was significant (P = 0.004) at the high dose. In these animals, 26% of the foci were classified as centrilobular whereas 37 and 39% of the foci were centrilobular in the low dose and control groups, respectively. Because of the co-localized nature of the changes in glutathione-associated enzymes and the decreased incidence of centrilobular foci, our results suggest that the reduced cellular environment may ultimately play a role in negatively selecting for foci growth.
Carcinogenesis 1998 Oct
PMID:Evidence for hepatocarcinogenic activity of pentachlorobenzene with intralobular variation in foci incidence. 980 69

Many chemical compounds which induce oxidative stress in the tissue produce carcinogenesis either alone or act as a tumor promoter in carcinogen-initiated animals after prolonged exposure. Here, we report that potassium bromate (KBrO3) induces renal proliferative response and damage by elaborating oxidative stress. KBrO3 administration dose dependently induced renal ornithine decarboxylase (ODC) activity several fold compared to its activity in saline-treated rats. Similarly renal DNA synthesis which has been measured as [3H]thymidine incorporation in DNA also increases. KBrO3 administration also depleted the level of renal glutathione and glutathione reductase activity in a time dependent manner. The maximum depletion in the levels of renal glutathione and glutathione reductase activity was observed 3 h after KBrO3 treatment which was 60 and 40%, respectively, of saline-treated controls. Parallel to these changes, a sharp increase in the blood urea nitrogen and serum creatinine levels was observed which is indicative of the concurrent renal damage. These results suggest that oxidant generating KBrO3 acts as a potent proliferator of kidney and acts by producing oxidative damage.
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PMID:Potassium bromate (KBrO3) induces renal proliferative response and damage by elaborating oxidative stress. 1009 27

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring compound shown to inhibit carcinogen-induced preneoplastic lesion formation in mouse mammary organ culture and tumorigenesis in the two-stage mouse skin model. Cancer chemopreventive potential was also suggested in various assays reflective of the three major stages of carcinogenesis. Anti-initiation activity was indicated by its antioxidant and antimutagenic effects, inhibition of the hydroperoxidase function of cyclooxygenase (COX), and induction of phase II drug-metabolizing enzymes. Antipromotion activity was indicated by antiinflammatory effects, inhibition of production of arachidonic acid metabolites catalyzed by either COX-1 or COX-2, and chemical carcinogen-induced neoplastic transformation of mouse embryo fibroblasts. Antiprogression activity was demonstrated by its ability to induce human promyelocytic leukemia (HL-60) cell differentiation. Moreover, pretreatment of mouse skin with resveratrol significantly counteracted 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress, as evidenced by numerous biochemical responses. Resveratrol reduced the generation of hydrogen peroxide, and normalized levels of myeloperoxidase and oxidized-glutathione reductase activities. It also restored glutathione levels and superoxide dismutase activity. As judged by the reverse transcriptase-polymerase chain reaction, resveratrol selectively inhibited TPA-induced expression of c-fos and transforming growth factor-beta 1 (TGF-beta 1), but did not affect other TPA-induced gene products including COX-1, COX-2, c-myc, c-jun, and tumor necrosis factor-alpha. These data indicate that resveratrol may interfere with reactive oxidant pathways and/or modulate the expression of c-fos and TGF-beta 1 to inhibit tumorigenesis in mouse skin. As reported herein, in addition to the activities described above, resveratrol inhibited the de novo formation of inducible nitric oxide synthase (iNOS) in mouse macrophages stimulated with lipopolysaccharide. This finding suggests an additional mechanism by which resveratrol may function as a cancer chemopreventive agent.
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PMID:Cancer chemopreventive activity of resveratrol. 1037 Aug 67

A significant depletion in the content of glutathione (GSH) and alteration in GSH redox system enzymes were observed in the lung of chrysotile-exposed animals (5 mg) during different developmental stages of asbestosis. In the alveolar macrophages (AM) of exposed animals, the depletion in GSH started from day 1 and reached a maximum at day 16, whereas in lung tissue the maximum depletion was observed when fibrosis has matured. It appears that cellular GSH depletion triggers oxidative stress in the system as observed from increased thiobarbituric acid reactive substance (TBARS) production and alteration in the activities of glutathione peroxidase (GPx), glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PD) and glutathione S-transferase (GST), the enzymes regulating oxidative tone. The depletion in GSH was also observed in red blood cells (RBC) of the exposed animals reaching a maximum when fibrosis matured. Thus the observed depletion in GSH, ascorbic acid and alteration in GSH redox system enzymes may be involved in fibrosis and carcinogenesis induced by chrysotile.
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PMID:Chrysotile-mediated imbalance in the glutathione redox system in the development of pulmonary injury. 1037 48

Isoflavones in soy may play a role in the prevention of cancer through their capacity to affect antioxidant or protective phase II enzyme activities. This study evaluated the effects of dietary isoflavone levels on the induction of antioxidant and phase II enzyme activities and inhibition of breast carcinogenesis. Female Sprague-Dawley rats (36 d) were fed one of four purified diets with casein, or with soy containing three levels of isoflavonoids (0.03, 0.4 or 0.81 mg/g diet; low, middle and high level of isoflavones, respectively). After 2 wk, enzyme activity was determined of rats (n = 6-7) from each diet group. Liver glutathione peroxidase and glutathione reductase activities, blood glutathione levels, kidney glutathione S-transferase and colon quinone reductase (QR) activities were greater in rats consuming the high isoflavone diet compared to rats consuming the casein diet. Kidney QR and liver, kidney, small intestine, and colon UDP-glucuronosyltransferase activities were greater in rats fed the high isoflavone diet compared to rats fed the casein and low-isoflavone diets. Liver and blood oxidized glutathione were lower in rats fed the high-isoflavone diet compared to those fed the low-isoflavone diet. A subset of rats (n = 86) was fed the purified diets for 2 wk and intubated with dimethylbenz[a]anthracene or peanut oil and palpated weekly for tumors. At 13 wk, there was an inverse relationship (R(2) = 0.911, P < 0.09) between tumor incidence and increasing isoflavone intake. These data support the mechanism of soy and soy isoflavones as antioxidant and phase II enzyme inducers, but not as tumor inhibitors.
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PMID:Soy induces phase II enzymes but does not inhibit dimethylbenz[a]anthracene-induced carcinogenesis in female rats. 1049 53

In recent years, considerable emphasis has been placed on identifying new cancer chemopreventive agents, which could be useful for the human population. Tephrosia purpurea has been shown to possess significant activity against hepatotoxicity, pharmacological and physiological disorders. Earlier we showed that Tephrosia purpurea inhibits benzoyl peroxide-mediated cutaneous oxidative stress and toxicity. In the present study, we therefore assessed the effect of Tephrosia purpurea on 12-O-tetradecanoyl phorbal-13-acetate (TPA; a well-known phorbol ester) induced cutaneous oxidative stress and toxicity in murine skin. The pre-treatment of Swiss albino mice with Tephrosia purpurea prior to application of croton oil (phorbol ester) resulted in a dose-dependent inhibition of cutaneous carcinogenesis. Skin tumor initiation was achieved by a single topical application of 7,12-dimethyl benz(a)anthracene (DMBA) (25 microg per animal per 0.2 ml acetone) to mice. Ten days later tumor promotion was started by twice weekly topical application of croton oil (0.5% per animal per 0.2 ml acetone, v /v). Topical application of Tephrosia purpurea 1 h prior to each application of croton oil (phorbol ester) resulted in a significant protection against cutaneous carcinogenesis in a dose-dependent manner. The animals pre-treated with Tephrosia purpurea showed a decrease in both tumor incidence and tumor yield as compared to the croton oil (phorbol ester)-treated control group. In addition, a significant reduction in TPA-mediated induction in cutaneous ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation was also observed in animals pre-treated with a topical application of Tephrosia purpurea. The effect of topical application of Tephrosia purpurea on TPA-mediated depletion in the level of enzymatic and non-enzymatic molecules in skin was also evaluated and it was observed that topical application of Tephrosia purpurea prior to TPA resulted in the significant recovery of TPA-mediated depletion in the level of these molecules, namely glutathione, glutathione S-transferase, glutathione reductase and catalase. From these data we suggest that Tephrosia purpurea can abrogate the tumor-promoting effect of croton oil (phorbol ester) in murine skin.
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PMID:Tephrosia purpurea alleviates phorbol ester-induced tumor promotion response in murine skin. 1124 14

The mechanism of arsenic toxicity is believed to be due to the ability of arsenite (As(III)) to bind protein thiols. Glutathione (GSH) is the most abundant cellular thiol, and both GSH and GSH-related enzymes are important antioxidants that play an important role in the detoxification of arsenic and other carcinogens. The effect of arsenic on the activity of a variety of enzymes that use GSH has been determined using purified preparations of glutathione reductase (GR) from yeast and bovine glutathione peroxidase (GPx) and equine glutathione S-transferase (GST). The effect on enzyme activity of increasing concentrations (from 1 microM to 100 mM) of commercial sodium arsenite (As(III)) and sodium arsenate (As(V)) and a prepared arsenic(III)-glutathione complex [As(III)(GS)(3)] and methylarsenous diiodide (CH(3)As(III)) has been examined. GR, GPx, and GST are not sensitive to As(V) (IC(50) > 50 mM), and none of the enzymes are inhibited or activated by physiologically relevant concentrations of As(III), As(III)(GS)(3), or CH(3)As(III), although CH(3)As(III) is the most potent inhibitor (0.3 mM < IC(50) < 1.5 mM). GPx is the most sensitive to arsenic treatment and GST the least. Our results do not implicate a direct interaction of As with the glutathione-related enzymes, GR, GPx, and GST, in the mechanism of arsenic toxicity. CH(3)As(III) is the most effective inhibitor, but it is unclear whether this product of arsenic metabolism is produced at a sufficiently high concentration in critical target tissues to play a major role in either arsenic toxicity or carcinogenesis.
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PMID:In vitro effect of arsenical compounds on glutathione-related enzymes. 1136 49

In an earlier communication, we have shown that Tephrosia purpurea ameliorates benzoyl peroxide-induced oxidative stress in murine skin (Saleem et al. 1999). The present study was designed to investigate a chemopreventive efficacy of T purpurea against N-diethylnitrosamine-initiated and potassium bromate-mediated oxidative stress and toxicity in rat kidney. A single intraperitoneal dose of N-diethylnitrosamine (200 mg/kg body weight) one hr prior to the dose of KBrO3 (125 mg/kg body weight) increases microsomal lipid peroxidation and the activity of xanthine oxidase and decreases the activities of renal antioxidant enzymes viz., catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase, phase II metabolizing enzymes such as glutathione-S-transferase and quinone reductase and causes depletion in the level of renal glutathione content. A sharp increase in blood urea nitrogen and serum creatinine has also been observed. Prophylactic treatment of rats with T. purpurea at doses of 5 mg/kg body weight and 10 mg/kg body weight prevented N-diethylnitrosamine-initiated and KBrO3 promoted renal oxidative stress and toxicity. The susceptibility of renal microsomal membrane for iron ascorbate-induced lipid peroxidation and xanthine oxidase activities were significantly reduced (P<0.01). The depleted levels of glutathione, the inhibited activities of antioxidant enzymes, phase II metabolizing enzymes and the enhanced levels of serum creatinine and blood urea nitrogen were recovered to a significant level (P<0.01). All the antioxidant enzymes were recovered dose-dependently. Our data indicate that T purpurea besides a skin antioxidant can be a potent chemopreventive agent against renal oxidative stress and carcinogenesis induced by N-diethylnitrosamine and KBrO3.
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PMID:Tephrosia purpurea ameliorates N-diethylnitrosamine and potassium bromate-mediated renal oxidative stress and toxicity in Wistar rats. 1145 68

The results of experiments on the subject of lipid peroxidation in hepatomas are described. It is now clear that lipid peroxidation is strongly decreased in most highly dedifferentiated hepatomas. It seems evident that the extent of the decline is strictly related to the degree of dedifferentiation. The model of diethylnitrosamine carcinogenesis, according to the method by Solt, Medline and Farber, has been now adopted to study the stages of carcinogenesis. It was shown that a net decline in lipid peroxidation occurs as early as at the stage of reversible nodules and progresses until the development of clear hepatomas. This change is practically simultaneous with a decline in the efficiency of the enzymes of the drug metabolizing system and in the content of cytochrome P450-Glutathione content and metabolism show also important changes. In fact, a dramatic increase in gamma-glutamyl-transpeptidase takes place very early during carcinogenesis, and is responsible for large decline in total glutathione during incubation of the homogenates. Glutathione peroxidase activity, on the contrary, is decreased, whereas glutathione reductase does not show significant changes. The supernatant of highly anaplastic tumors inhibits lipid peroxidation in normal liver homogenates, suggesting the presence of substances provided with antioxidant properties. These cannot be, however, related to a higher glutathione content. Supernatants from early nodules seem to be unable to block lipid peroxidation in normal liver homogenates. Preliminary experiments done to study the aldehyde pattern produced during lipid peroxidation, both in hepatomas and in nodules, confirm the presence of very poor lipid peroxidation and possibly of different peroxidation kinetics.
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PMID:Further experiments on lipid peroxidation in transplanted and experimental hepatomas. 1147 22

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