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

In the mouse embryo cell line BALB/3T3 Clone A31-1-1, dose-dependent morphologic neoplastic transformation was obtained with NaAsO2, Na2HAsO4, CdCl2, and K2CrO4. Cellular uptake was four fold higher for As3+ than for As5+, and As5- was metabolized to As3+ in cytosol. Cytotoxicity and transformation rates were four fold higher for As3+ than As5+, but when correlated to cellular As burden they were equivalent. As3+ appears responsible for the transforming activity. The foci transformed by metals (or by other carcinogens) gave rise to tumorigenic cell lines (sc sarcomas in nude mice), none of which, however, induced metastases when tested by sc or by iv injection in nude mice. Thus carcinogens change this aneuploid cell line from a preneoplastic stage to the expression of malignant growth but not of metastatic activity. Metastatic and type IV collagenolytic activities can be induced by transfection of the c-Ha-ras oncogene and inhibited by the Ad2-E1a gene (so far shown in other cell types). It remains to be seen whether metal or other carcinogens can induce the nonmetastatic phenotype to become metastatic. The molecular mechanisms of metal carcinogenesis, studied in cell culture systems, in combination with other factors or oncogenes, may reveal the effect of individual metal carcinogens on discrete steps of the complex process of carcinogenesis.
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PMID:Neoplastic transformation of BALB/3T3 cells by metals and the quest for induction of a metastatic phenotype. 248 30

Sodium arsenite and sodium arsenate were observed to induce morphological transformation of Syrian hamster embryo cells in a dose-dependent manner. A linear dose-dependence with a slope of approximately 1 was observed with both compounds when the data were plotted on a log-log graph. The trivalent sodium arsenite was greater than 10-fold more potent than the pentavalent sodium arsenate. The compounds also exhibited toxicity; however, transformation was observed at non-toxic as well as toxic doses. At low doses, enhanced colony-forming efficiency of the cells was observed. To understand the mechanism of arsenic-induced transformation, the genetic effects of the two arsenicals were examined over the same doses that induced transformation. No arsenic-induced gene mutations were detected at two genetic loci. However, cell transformation and cytogenetic effects, including endoreduplication, chromosome aberrations, and sister chromatid exchanges were induced by the arsenicals with similar dose-responses. These results support a possible role for chromosomal changes in arsenic-induced transformation.
Carcinogenesis 1985 Oct
PMID:Comparison of arsenic-induced cell transformation, cytotoxicity, mutation and cytogenetic effects in Syrian hamster embryo cells in culture. 384 60

Sodium arsenite (As)-induced DNA damage was measured in human fetal lung fibroblasts (2BS cells) by an alkaline elution technique and a fluorometric DNA assay. Sodium arsenite at 1-5 microM produced DNA-protein crosslinks, while at 10 microM this effect was not observed. Deproteinization of DNA-protein complexes revealed protein-associated DNA-strand breaks. Both DNA-protein crosslinks and DNA-strand breaks were concentration-dependent; 3 microM As was the most efficient dose. Arsenic mediated DNA-protein interactions may play a major role in arsenic carcinogenesis, and the induced protein-associated DNA-strand breaks could provide an explanation for chromosome aberrations and sister-chromatid exchanges induced by arsenic in vivo and in vitro.
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PMID:Arsenic-induced DNA-strand breaks associated with DNA-protein crosslinks in human fetal lung fibroblasts. 768 11

Sodium arsenite and cadmium chloride, were administered orally to adult female rats at 21 and 4 h prior to sacrifice. Liver, lung, skin and urinary bladder were the tissues studied. DNA damage, cytochrome P450, glutathione content (GSH), ornithine decarboxylase (ODC), serum alanine aminotransferase and heme oxygenase activity were measured. Sodium arsenite increased rat hepatic ODC activity at 1.6 and 24.6 mg/kg and hepatic heme oxygenase activity at 8.2 and 24.6 mg/kg, but did not cause any DNA damage. Cadmium chloride did not affect any of the six parameters tested. These findings suggest that sodium arsenite may be a promoter rather than an initiator of carcinogenesis.
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PMID:Arsenite, but not cadmium, induces ornithine decarboxylase and heme oxygenase activity in rat liver: relevance to arsenic carcinogenesis. 855 13

Arsenic, a well-known human carcinogen present as a contaminant in ground water poses a serious threat to public health in various countries. The anticlastogenic properties of two dietary supplements, garlic and mustard oil, were screened against the clastogenic activity of sodium arsenite, since diet may contain factors which affect the process of mutagenesis and carcinogenesis. Aqueous extract of garlic (100 mg/kg b.w.) and mustard oil (0.643 mg/kg b.w.) were fed to Mus musculus for 30 consecutive days either singly or simultaneously. Sodium arsenite (0.1 mg/kg b.w.) was injected subcutaneously on days 7, 14, 21 and 30 of the experiment, singly and together with the dietary supplements. The animals were sacrificed 24 h after the last exposure to sodium arsenite and clastogenic effects were observed in the bone marrow cells. The degree of modulation of sodium arsenite-induced chromosomal aberrations was more pronounced in mustard oil than in garlic extract and simultaneous administration of both the dietary supplements reduced the clastogenic effects of sodium arsenite closer to the level of the negative control. The greater efficacy could be due to the interaction of the two dietary supplements and its radical scavenging property.
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PMID:Mustard oil and garlic extract as inhibitors of sodium arsenite-induced chromosomal breaks in vivo. 945 73

Arsenic is an established human carcinogen. Deficiencies in available animal models have inhibited a detailed analysis of the mechanism of arsenic induced cancer. This study sought to determine the role of a methyl-deficient diet in combination with sodium arsenite on the genomic methylation status and Ha-ras methylation status of C57BL/6J male mice hepatic DNA. Mice were administered arsenic as sodium arsenite via drinking water at 0, 2.6, 4.3, 9.5 or 14.6 mg sodium arsenite/kg/day. Administration occurred 7 days a week for 130 days. Dose-related effects on the liver were evident in mice administered arsenic and methyl-deficient diets. Most prominent were observations of steatosis and microgranulomas. Sodium arsenite increased genomic hypomethylation in a dose dependent manner and methyl-deficiency and sodium arsenite reduced the frequency of methylation at several cytosine sites within the promoter region of the oncogenic gene, Ha-ras. Methylation changes were prominent in a 500 bp non-CpG island-like region of the Ha-ras promoter and less prominent in a 525 bp CpG island-like region. DNA methylation plays an important role in the physiological expression of many genes including Ha-ras. Significantly reduced methylation at a key regulatory region of Ha-ras in the mouse liver may have relevance to understanding arsenic-induced perturbations in the methylation patterns of cellular growth genes involved in the formation of tumors. These findings highlight the effect of sodium arsenite on inherent methylation processes within the hepatic cell.
Carcinogenesis 2002 May
PMID:Sodium arsenite administration via drinking water increases genome-wide and Ha-ras DNA hypomethylation in methyl-deficient C57BL/6J mice. 1201 50

Arsenic is a recognized human carcinogen and development of rodent models remains a critically important research objective. Since gestation can be a period of high sensitivity to chemical carcinogenesis, we have performed a series of transplacental carcinogenicity studies in mice with inorganic arsenic. In this study, groups of pregnant C3H mice received drinking water containing sodium arsenite (NaAsO2) at 0, 42.5 and 85 p.p.m. arsenic ad libitum from days 8 to 18 of gestation. These doses of arsenic were well tolerated. Dams delivered normally and at weaning (4 weeks) offspring were randomly put into groups (n = 25) of males or females according to maternal dose. In an attempt to promote skin cancers initiated by transplacental arsenic, duplicate groups of control or arsenic exposed offspring were topically exposed to 12-O-tetradecanoyl phorbol-13-acetate (TPA; 2 micro g/0.1 ml acetone, twice/week) from 4 to 25 weeks of age. Irrespective of TPA exposure, male offspring showed arsenic-induced dose-related increases in hepatocellular carcinoma incidence and multiplicity, as well as increases in adrenal tumor incidence and multiplicity. In female offspring, an increase in epithelial ovarian tumors occurred with arsenic exposure regardless of TPA exposure. Females also showed pre-neoplastic lesions of the reproductive tract, including hyperplasia of the uterus and oviduct, after arsenic but independent of TPA exposure. Although TPA had no effect on skin tumors, it promoted arsenic initiated liver tumors in females and lung tumors in both sexes. Thus, inorganic arsenic, as a single agent, can consistently act as a complete transplacental carcinogen in mice, inducing tumors at multiple sites, and as a tumor initiator in some tissues. Skin tumors were not initiated by arsenic in mouse fetuses possibly indicating tissue-specific mechanisms of action. This study indicates that gestation is a period of high sensitivity to arsenic carcinogenesis.
Carcinogenesis 2004 Jan
PMID:Induction of tumors of the liver, lung, ovary and adrenal in adult mice after brief maternal gestational exposure to inorganic arsenic: promotional effects of postnatal phorbol ester exposure on hepatic and pulmonary, but not dermal cancers. 1451 61

Sodium arsenite is much more potent than sodium arsenate in producing adverse effects in animals and in cultured cells. Although arsenate may exhibit toxicity as a phosphate analogue, its potency in vivo appears to be enhanced by reduction to arsenite. To understand the relative importance of this reduction, which is critical in evaluating the responsiveness of cell culture models to the different oxidation states and thus to elucidating the mechanism of arsenic action, present work has correlated the extent of reduction with biological activity in human keratinocytes. The results show that at biologically relevant concentrations, arsenate reduction to appreciable levels required several days, helping rationalize a previous empirical observation that it was approximately one-third as potent as arsenite. The relatively low conversion rate also emphasizes a limitation of culture; arsenate was nearly as efficacious as arsenite, but the time required for it to reach maximal effect exceeded ordinary medium change intervals. In keratinocytes, an important role for purine nucleoside phosphorylase in the reduction could not be demonstrated, indicating that another pathway is dominant in this cell type. Methylation of inorganic arsenic, uptake of methylated forms, and their reduction were all very slow. These findings suggest that the reduced methylated forms have only a small contribution to skin carcinogenesis unless they are supplied through the circulation. In parallel experiments, trivalent antimony was similar to arsenite in potency and efficacy, whereas pentavalent antimony was virtually without biological effect. Conversion of antimony in the pentavalent to the trivalent oxidation state was not detectable in keratinocytes. These findings emphasize the importance of intracellular reduction of the metalloids for biological effects.
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PMID:Biological activity of inorganic arsenic and antimony reflects oxidation state in cultured human keratinocytes. 1468 Mar 77

Exposure to arsenic (As) is a risk factor for the development of diabetes, vascular diseases and cancer. Several theories have been proposed to account for the mechanisms potentially responsible for As toxicity and carcinogenesis. Currently, we have investigated whether the eukaryotic translation initiation factor 4E (eIF4E), the mRNA cap binding and rate limiting factor required for translation, is a target for As-induced cytotoxicity and cell death. We have also investigated the potential cellular mechanisms underlying the As-induced de-regulation of expression of eIF4E that are most likely responsible for the cytotoxicity and cell death induced by As. Exposure of four different human cell lines - HCT15 (colorectal adenocarcinoma), PLC/PR/5 (hepatocellular carcinoma), HeLa (cervical adenocarcinoma) and Chang (likely derived from HeLa cells) to sodium arsenite (NaAsO2) for time intervals up to 24 h resulted in a concentration-dependent cytotoxicity and cell death. All the NaAsO2-treated cells exhibited significant inhibition of eIF4E gene (protein). The potential involvement of eIF4E gene expression in the NaAsO2-induced cytotoxicity and cell death was investigated by silencing the cellular expression of the eIF4E gene by employing a small interfering RNA (SiRNA) specifically targeting the eIF4E gene's expression. The SiRNA-mediated silencing of eIF4E gene expression also resulted in significant cytotoxicity and cell death suggesting that the toxicity noticed among the NaAsO2-treated cells was probably due to the chemically induced inhibition of eIF4E gene expression. The potential involvement of inhibition of eIF4E gene expression in the NaAsO2-induced cytotoxicity and cell death was further investigated by employing transgenic cell lines overexpressing the eIF4E gene. Overexpression of the eIF4E gene in the Chinese hamster ovary cell line was protective against the NaAsO2-induced cytotoxicity and cell death. Additional studies conducted to understand the potential mechanisms responsible for NaAsO2-induced inhibition of eIF4E gene expression demonstrated that exposure to NaAsO2 resulted in transcriptional down-regulation of the eIF4E gene only in HCT-15 and HeLa cells, while in the NaAsO2-treated and PLC/PR/5 and Chang cells, the eIF4E mRNA expression level was comparable to those of the corresponding control cells. Cellular levels of ubiquitin and the process of ubiquitination were significantly higher in the NaAsO2-treated cells compared with the control cells. Immunoprecipitation of lysates obtained from the NaAsO2-treated cells and the subsequent western blot analysis of the immunoprecipitated protein(s) using the eIF4E antibody detected the presence of eIF4E protein in the immunoprecipitate suggesting possible ubiquitination of eIF4E protein in the NaAsO2-treated cells. Pre-exposure of the NaAsO2-treated cells to proteasome inhibitors blocked the inhibition of eIF4E gene expression as well as the resulting cytotoxicity and cell death. Furthermore, exposure of cells to NaAsO2 resulted in a significant inhibition of expression of the cell cycle and growth regulating gene, cyclin D1. Whether or not the inhibition of cyclin D1 in the NaAsO2-treated cells is mediated through the inhibition of eIF4E was tested by silencing the expression of eIF4E gene in the cells. Transfection of cells with SiRNA specifically targeting eIF4E gene expression resulted in a significant inhibition of cyclin D1 gene suggesting that the observed inhibition of cyclin D1 gene in the NaAsO2-treated cells is most likely mediated through inhibition of eIF4E gene. Taken together, our results indicate that the exposure of cells to NaAsO2 resulted in cytotoxicity and cell death, at least in part, due to the inhibition of eIF4E gene expression leading to diminished cellular levels of critical genes such as cyclin D1.
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PMID:Sodium arsenite-induced inhibition of eukaryotic translation initiation factor 4E (eIF4E) results in cytotoxicity and cell death. 1628 21

Arsenic is widely distributed in the environment, and it is a proven toxic and carcinogenic agent. On the southwest coast of Taiwan, an endemic occurrence of chronic arsenical poisoning due to a high concentration of arsenic in artesian-well water has been reported. However, the mechanisms of its carcinogenic action are still unclear. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is an essential cascade for mediating normal functions of different cytokines in the development of the hematopoietic and immune systems. In this study, the substantial morphological changes observed in SV-40 immortalized human uroepithelial cells (SV-HUC-1) after treatment of various concentrations of arsenite were examined, and the expression of Bcl-6, Jak-2 and p-STAT3 (Tyr 705) were evaluated by immunocytochemistry and Western blotting. Our results showed that the expression of Bcl-6 increased dose-dependently in arsenite-treated urothelial cells. Sodium arsenite treatment reduced Jak-2 protein expression in a dose-dependent manner. However, treatment of SV-HUC-1 cells with arsenite at concentration ranges from 2 and 4microM for 48h dramatically increased p-STAT3 (Tyr 705), but the levels decreased at 8-40microM of arsenite. Our data suggest that arsenic-mediated inactivation of the JAK-STAT signaling pathway might be caused by Bcl-6 interaction with JAK tyrosine kinase or STAT. In conclusion, our findings indicate that arsenic inhibits JAK tyrosine kinase protein expression and suggest the interference in the JAK-STAT pathway might be through Bcl-6 playing an important role in arsenic-associated carcinogenesis.
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PMID:Expression of STAT3 and Bcl-6 oncoprotein in sodium arsenite-treated SV-40 immortalized human uroepithelial cells. 1768 8


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