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Query: UMLS:C0596263 (carcinogenesis)
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The protective effect of Brazilian propolis and its extract Artepillin C against ferric nitrilotriacetate (Fe-NTA)-induced renal lipid peroxidation and carcinogenesis was studied in male ddY mice. Fe-NTA-induced renal lipid peroxidation leads to a high incidence of renal cell carcinoma (RCC) in mice. Administration of propolis by gastric intubation 2 h before or Artepillin C at either the same time, 2 h, or 5 h before the intraperitoneal injection of Fe-NTA (7 mg Fe/kg) effectively inhibited renal lipid peroxidation. This was evaluated from the measurement of renal thiobarbituric acid-reactive substances (TBARS) or histochemical findings of 4-hydroxy-2-nonenal (4-HNE)-modified proteins and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Repeated injection of Fe-NTA (10 mg Fe/kg per day, twice a week for a total of 16 times in 8 weeks) caused subacute nephrotoxicity as revealed by necrosis and pleomorphic large nuclear cells in the renal proximal tubules, and gave rise to RCC 12 months later. A protective effect from carcinogenicity was observed in mice given propolis or Artepillin C. Furthermore, the mice given Fe-NTA only developed multiple cysts composed of precancerous lesions with multilayered and proliferating large atypical cells. Mice treated with propolis and Artepillin C also had cysts, but these were dilated and composed of flat cells. These results suggest that propolis and Artepillin C prevent oxidative renal damage and the carcinogenesis induced by Fe-NTA in mice.
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PMID:Renal carcinogenesis induced by ferric nitrilotriacetate in mice, and protection from it by Brazilian propolis and artepillin C. 1101 80

In experiments using the renal carcinogen ferric nitrilotriacetate (Fe-NTA) in male ddY mice, primary pulmonary cancers were also induced in bronchiolar and alveolar tissues. 4-Hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), products of oxidative processes, increased in bronchiolar and alveolar cells after administration of Fe-NTA. These substances disappeared after oral administration of propolis or artepillin C, as shown histochemically, and correlated with an anticancer prophylactic effect of propolis and artepillin C. From our investigation, lipid peroxidation seems to play an important role in pulmonary carcinogenesis. Malignant progression from adenoma of bronchiolar or alveolar origin to malignant tumors has been proposed to involve a stepwise transformation. In our study, adenomas developed into adenocarcinomas and large cell carcinomas after treatment with Fe-NTA. In contrast, after oral administration of propolis or artepillin C, adenomas did not progress to carcinomas. Instead of developing into large cell cancers, as induced by Fe-NTA in control mice, adenomas showed remarkable proliferation of macrophages and local anti-oxidant activity after treatment with either propolis or artepillin C. Propolis and artepillin C therefore appear to inhibit lipid peroxidation and the development of pulmonary cancers.
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PMID:Pulmonary carcinogenesis induced by ferric nitrilotriacetate in mice and protection from it by Brazilian propolis and artepillin C. 1131 23

Administration of ferric nitrilotriacetate (Fe-NTA) in vivo causes acute renal tubular injury and finally induces renal cell carcinoma. There is accumulating evidence that these processes involve free radicals generated by Fe-NTA. To study the mechanism of renal carcinogenesis by Fe-NTA, we attempted to induce malignant transformation of primary cultured renal cells by treatment with Fe-NTA. When primary cultured renal cells (PRC) were treated continuously with Fe-NTA, all of the PRC died without transformation. On the other hand, when PRC were treated intermittently with Fe-NTA, transformed epithelial colonies were observed at 3 weeks after the first treatment. The established transformed cell line (RK523) showed drastic morphological transformation, grew in soft agar, and formed tumors when transplanted into athymic nude mice. These results indicate that the balance between cytotoxicity and mutagenecity is important for Fe-NTA induced transformation. The RK523 cell line may be a useful model for studying renal carcinogenesis in vitro.
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PMID:In vitro transformation of rat renal cells by treatment with ferric nitrilotriacetate. 1133 5

Oxidative tissue damage has been shown to be associated with carcinogenesis. In human cancers p16(INK4A) is one of the most frequently mutated tumor suppressor genes. The present study used the ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model to determine whether oxidative damage can cause specific allelic loss of p16 (INK4A). By the use of fluorescent in situ hybridization in combination with imprint cytology at single-cell resolution, we found that the number of renal tubular cells with aneuploidy (1 or 3 signals) at the p16(INK4A) locus was significantly and specifically increased (1 week, 37.2 +/- 2.3%; 3 weeks, 37.8 +/- 1.3% vs control, 22.5 +/- 1.9%; mean +/- SE, N = 8; P < 0.001 and P < 0.0001, respectively) after repeated intraperitoneal administration of 5 to10 mg of iron/kg in the form of Fe-NTA for 3 weeks. No increase in aneuploidy was observed at the loci of either the p53 or vhl tumor suppressor gene. Furthermore, the increase in the cells with 3 signals was followed by a continuous increase in those with 1 signal. Therefore, the p16 (INK4A) locus is specifically vulnerable to oxidative damage, leading to its allelic loss within weeks, presumably due to a deficiency in the replication of both the alleles.
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PMID:Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis. 1183 58

An iron chelate, ferric nitrilotriacetate (Fe-NTA), is a potent nephrotoxic agent, and induces acute and subacute renal proximal tubular necrosis, a consequence of the Fenton-like reaction that eventually leads to a high incidence of renal adenocarcinoma in rodents. In order to examine the possible mechanism for carcinogenic activity, we investigated the DNA damage with Fe-NTA in the presence of various peroxides/organic hydroperoxides. S1 nuclease hydrolysis and deoxyribose degradation assays were performed. Incubation of calf thymus DNA with ferric nitrilotriacetate (0.1 mM) in the presence of peroxides/organic hydroperoxides at a final concentration of 40 mM of each in phosphate buffer (0.1 M, pH 7.4) augmented DNA damage severalfold as compared to the damage caused by individual treatments. Fe-NTA in the presence of hydrogen peroxide caused DNA single-strand breaks and damage to its deoxyribose sugar moiety as measured, respectively, by S1 nuclease hydrolysis and deoxyribose degradation using calf thymus DNA. However, only deoxyribose degradation could be recorded in the presence of other peroxide/organic hydroperoxides. No DNA single-strand break was observed by this treatment. The observed differences in DNA damage by hydrogen peroxide and organic hydroperoxides/peroxide have been ascribed to the differential reactivity of DNA with hydroxyl and alkoxy/aryloxy free radicals produced, respectively, from these inorganic and organic peroxides. These studies suggest that Fe-NTA not only mediated the production of reactive oxygen species, but also catalysed the decomposition of these peroxides and organic hydroperoxides, which may cause a clastogenic change in DNA. This reactivity enhances the clastogenic activity in DNA. These changes in the DNA structure may ultimately be responsible, at least in part, for the induction of carcinogenesis in Fe-NTA-exposed animals.
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PMID:Differential role of hydrogen peroxide and organic hydroperoxides in augmenting ferric nitrilotriacetate (Fe-NTA)-mediated DNA damage: implications for carcinogenesis. 1261 93

A number of investigations have implicated the involvement of free radicals in various pathogenic process including initiation/promotion stages of carcinogenesis and antioxidants have been considered to be a protective agent for this reason. An iron chelate, ferric nitrilotriacetate (Fe-NTA), is a potent nephrotoxic agent and induces acute and subacute renal proximal tubular necrosis by catalyzing the decomposition of hydrogen peroxide-derived production of hydroxyl radicals, which are known to cause lipid peroxidation and DNA damage. The latter is associated with a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation and DNA damage are the principal manifestation of Fe-NTA-induced toxicity, which could be mitigated by antioxidants. In this study, we therefore investigated the effect of curcumin, a polyphenolic compound from Curcuma longa for a possible protection against lipid peroxidation and DNA damage induced by Fe-NTA and hydrogen peroxide in vitro. Incubation of renal microsomal membrane/and or calf thymus DNA with hydrogen peroxide (40 mM) in the presence of Fe-NTA (0.1 mM) induces renal microsomal lipid peroxidation and DNA damage to about 2.2-and 5.6-fold, respectively, as compared to saline treated control (P<0.001). Induction of renal microsomal lipid peroxidation and DNA damage was modulated by curcumin dose dependently. In lipid peroxidation protection studies, curcumin treatment showed a dose-dependent strong inhibition (18-80% inhibition, P<0.05-0.001) of Fe-NTA and hydrogen peroxide-induced lipid peroxidation as measured by MDA formation in renal microsomes. Similarly, in DNA-sugar damage protection studies, curcumin treatment also showed a dose dependent inhibition (22-57% inhibition, P<0.05-0.001) of DNA-sugar damage. From these studies, it was concluded that curcumin modulates Fe-NTA and hydrogen peroxide-induced peroxidation of microsomal membrane lipids and DNA damage. Curcumin might, therefore, be a suitable candidate for the chemoprevention of Fe-NTA-associated cancer.
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PMID:In vitro curcumin modulates ferric nitrilotriacetate (Fe-NTA) and hydrogen peroxide (H2O2)-induced peroxidation of microsomal membrane lipids and DNA damage. 1261 5

Cancer chemoprevention is the use of chemical agents to inhibit, delay or reverse carcinogenesis. We established a novel method to evaluate agents for use in the chemoprevention of reactive oxygen species (ROS)-associated cancer. Induction of renal cell carcinoma in rats by ferric nitrilotriacetate (Fe-NTA) is an established model of ROS-associated cancer. We recently identified the p16INK4A tumor suppressor gene as one of the major target genes in this model, and showed by the use of in situ hybridization that allelic loss of p16IK4A occurs in the increased fraction of renal tubular cells within a few weeks. In the present study, we tested whether diets including green tea powder or a processed grain food are effective chemopreventive agents in this animal model. Consumption of these modified diets led to a significant decrease in the fraction of aneuploid cells after 1 week of repeated Fe-NTA administration. A decrease in renal lipid peroxidation after a single administration of Fe-NTA was also observed. Therefore, intake of green tea or processed grain foods stabilizes p16INK4A in the genome, at least in this model, and might be helpful for the prevention of ROS-associated cancer. This novel method is versatile, and may work as a surrogate end-point biomarker for screening the usefulness of agents for cancer chemoprevention.
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PMID:Novel surrogate end-point biomarker to evaluate agents for use in the chemoprevention of reactive oxygen species-associated cancer. 1268 24

Ferric nitrilotriacetate (Fe-NTA) induces oxidative renal damage leading to a high incidence of renal cell carcinoma (RCC) in rats. Differential display analysis of such RCCs revealed elevated expression of annexin 2 (Anx2), a substrate for kinases and a receptor for tissue-type plasminogen activator and plasminogen. We conducted this study to clarify the significance of Anx2 in Fenton reaction-based carcinogenesis. Messenger RNA and protein levels of Anx2 were increased time-dependently in the rat kidney after Fe-NTA administration as well as in LLC-PK1 cells after exposure to H2O2. The latter was inhibited by pretreatment with N-acetylcysteine, pyrrolidine dithiocarbamate or catalase. Immunohistochemistry revealed negligible staining in the normal renal proximal tubules, but strong staining in regenerating proximal tubules, karyomegalic cells and RCCs. Metastasizing RCCs showed higher Anx2 protein levels. Anx2 was phosphorylated at serine and tyrosine residues in these cells and coimmunoprecipitated with phosphorylated actin. Overexpression of Anx2 induced a higher cell proliferation rate in LLC-PK1 cells. In contrast, a decrease in proliferation leading to apoptosis was observed after Anx2 antisense treatment to cell lines established from Fe-NTA-induced RCCs. These results suggest that Anx2 is regulated by redox status, and that persistent operation of this adaptive mechanism plays a role in the proliferation and metastasis of oxidative stress-induced cancer.
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PMID:Redox regulation of annexin 2 and its implications for oxidative stress-induced renal carcinogenesis and metastasis. 1504 81

Probucol, a clinically used cholesterol lowering and antioxidant drug, was investigated for possible protection against lipid peroxidation and DNA damage induced by iron nitrilotriacetate (Fe-NTA) plus hydrogen peroxide (H2O2). Fe-NTA is a potent nephrotoxic agent and induces acute and subacute renal proximal tubular necrosis by catalyzing the decomposition of H2O2-derived production of hydroxyl radicals, which are known to cause lipid peroxidation and DNA damage. Fe-NTA is associated with a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation and DNA damage are the principal manifestation of Fe-NTA induced toxicity, which could be mitigated by probucol. Incubation of renal microsomal membrane and/or calf thymus DNA with H2O2 (40 mM) in the presence of Fe-NTA (0.1 mM) induces renal microsomal lipid peroxidation and DNA damage to about 2.4-fold and 5.9-fold, respectively, as compared to control (P < 0.05). Induction of renal microsomal lipid peroxidation and DNA damage was inhibited by probucol in a concentration-dependent manner. In lipid peroxidation protection studies, probucol treatment showed a concentration-dependent inhibition (10-34% inhibition; P < 0.05) of Fe-NTA plus H2O2-induced lipid peroxidation as measured by thiobarbituric acid reacting species' (TBARS) formation in renal microsomes. Similarly, in DNA damage protection studies, probucol treatment also showed a concentration-dependent strong inhibition (36-71% inhibition; P < 0.05) of DNA damage. From these studies, it was concluded that probucol inhibits peroxidation of microsomal membrane lipids and DNA damage induced by Fe-NTA plus H2O2. However, because the lipid peroxidation and DNA damage studied here are regarded as early markers of carcinogenesis, we suggest that probucol may be developed as a cancer chemopreventive agent against renal carcinogenesis and other adverse effects of Fe-NTA exposure in experimental animals, in addition to being a cholesterol-lowering drug, useful for the control of hypercholestrolemia.
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PMID:Probucol as a potent inhibitor of oxygen radical-induced lipid peroxidation and DNA damage: in vitro studies. 1532 47

In an earlier communication we reported that Nigella sativa suppresses potassium bromate-induced renal oxidative damage. In the present study, we report the chemopreventive effect of Nigella sativa against ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative stress, hyperproliferative response and renal carcinogenesis. Fe-NTA (9 mg Fe/kg body weight, intraperitoneally) enhances renal lipid peroxidation, xanthine oxidase, gamma-glutamyl transpeptidase and hydrogen peroxide (H2O2) generation with reduction in renal glutathione content, antioxidant enzymes and phase II metabolizing enzymes. It also caused increase in blood urea nitrogen, serum creatinine, ornithine decarboxylase (ODC) activity and thymidine [H] incorporation into renal DNA. It also enhanced DEN (N-diethylnitrosamine)-initiated renal carcinogenesis by increasing the percentage incidence of tumours. Treatment of rats orally with Nigella sativa (50 and 100 mg/kg body weight) resulted in significant decrease in gamma-glutamyl transpeptidase, lipid peroxidation, xanthine oxidase, H2O2 generation, blood urea nitrogen, serum creatinine, renal ODC activity, DNA synthesis (P<0.001) and incidence of tumours. Renal glutathione content (P<0.01), glutathione-metabolizing enzymes (P<0.001) and antioxidant enzymes were also recovered to significant levels (P<0.001). Thus, our data suggest that Nigella sativa is a potent chemopreventive agent and suppresses Fe-NTA-induced oxidative stress, hyperproliferative response and renal carcinogenesis in Wistar rats.
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PMID:Inhibition of two stage renal carcinogenesis, oxidative damage and hyperproliferative response by Nigella sativa. 1578 20


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