Effects of caffeine on glandular stomach carcinogenesis induced in rats by N-methyl-N′-nitro-N-nitrosoguanidine and sodium chloride

doi:10.1016/0278-6915(95)80243-6

Food and Chemical Toxicology

Volume 33, Issue 1, January 1995, Pages 21-26

https://doi.org/10.1016/0278-6915(95)80243-6 Get rights and content

Abstract

The modifying effects of caffeine ingestion on glandular stomach carcinogenesis induced by N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and sodium chloride (NaCl) were investigated in male Wistar rats. Animals were given a MNNG solution (100 ppm) as their drinking water and simultaneously fed a diet supplemented with 5% NaCl for 8 wk. They then received 0.25% caffeine solution (groups 1 and 3) or tap water (groups 2 and 4) as the drinking water, and were fed the NaCl diet (groups 1 and 2) or basal diet (groups 3 and 4) for the following 32 wk. Both caffeine and NaCl treatments exerted growth retardation effects, the suppression being stronger with caffeine than NaCl, and animals in group I (NaCl plus caffeine) showing the lowest body weight. The incidence of adenocarcinomas in the pylorus was significantly decreased in group 1 compared with the group 2 (NaCI) value (P < 0.05). The incidence of atypical hyperplasias in the fundus was also lower in group 1 than in group 2, although in both cases significantly higher (P < 0.05 and P < 0.01) than in group 4 (no treatment). These results were in good agreement with short-term assay findings whereby lipid peroxidation in the glandular stomach mucosa induced by 4% NaCl ingestion was inhibited by caffeine treatment. In group 3 (caffeine), caffeine intake by itself did not modulate glandular stomach tumour development. The results thus suggest that caffeine inhibits the gastric tumour promotion activity of NaCl in rats.

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Drinking for protection? Epidemiological and experimental evidence on the beneficial effects of coffee or major coffee compounds against gastrointestinal and liver carcinogenesis
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Citation Excerpt :
As in animal studies on oral and esophageal carcinogenesis, there are few animal studies on the effects of caffeine or chlorogenic acid on gastric carcinogenesis (Table 4). Nishikawa et al. (1995) observed that caffeine treatment reduced the incidence of pyloric AC and lipid hydroperoxide levels in the gastric mucosa of male Wistar rats submitted to MNNG and NaCl-induced carcinogenesis. Ultimately, the chlorogenic acid treatment led to a reduction of the incidence of MNU-induced adenomatous hyperplasia and AC, as well as to a decrease in proliferating cell nuclear antigen (PCNA) labeling indexes in non-neoplastic glandular areas (Shimizu et al., 1999).
Recent meta-analyses indicate that coffee consumption reduces the risk for digestive tract (oral, esophageal, gastric and colorectal) and, especially, liver cancer. Coffee bean-derived beverages, as the widely-consumed espresso and “common” filtered brews, present remarkable historical, cultural and economic importance globally. These drinks have rich and variable chemical composition, depending on factors that vary from “seeding to serving”. The alkaloids caffeine and trigonelline, as well as the polyphenol chlorogenic acid, are some of the most important bioactive organic compounds of these beverages, displaying high levels in both espresso and common brews and/or increased bioavailability after consumption. Thus, we performed a comprehensive literature overview of current knowledge on the effects of coffee beverages and their highly bioavailable compounds, describing: 1) recent epidemiological and experimental findings highlighting the beneficial effects against gastrointestinal/liver carcinogenesis, and 2) the main molecular mechanisms in these in vitro and in vivo bioassays. Findings predominantly address the protective effects of coffee beverages and their most common/bioavailable compounds individually on gastrointestinal and liver cancer development. Caffeine, trigonelline and chlorogenic acid modulate common molecular targets directly implicated in key cancer hallmarks, what could stimulate novel translational or population-based mechanistic investigations.
Evaluation of anticancer effects and enhanced doxorubicin cytotoxicity of xanthine derivatives using canine hemangiosarcoma cell lines
2013, Research in Veterinary Science
Citation Excerpt :
Caffeine and theophylline, a methylxanthine derivative (Fig. 1), increase cAMP by inhibiting phosphodiesterase activity and are well known to have diuretic, cardiac, and central nervous system stimulatory effects. In addition, recent studies have revealed in cultured rat and human cells that caffeine inhibits human tumor colony formation in vitro (Tomita and Tsuchiya, 1989) and the development of tumors in vivo induced by various carcinogens in numerous organs including skin (Huang et al., 1997), lung (Lu et al., 2006), stomach (Nishikawa et al., 1995) and liver (Hosaka et al., 1984). Caffeine is an inhibitor of ataxia telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) kinases, which are master regulators of DNA damage-induced cell cycle checkpoints (Zhou et al., 2000).
Methylxanthine derivatives increase cAMP and are known to have diuretic, cardiac, and central nervous system stimulatory effects. Moreover, caffeine inhibits the development of tumors induced by various carcinogens. The aim of this work was to elucidate the anticancer effects on apoptosis of xanthine derivatives alone and with doxorubicin in canine hemangiosarcoma cells. Xanthine derivatives with or without doxorubicin were administered to cells, and the effects were investigated by measuring tumor cell proliferation, cell death (cytotoxicity) induction, and apoptosis by the expression of annexin V or caspase 3/7. Both caffeine and theophylline induced apoptosis, and the treated cells expressed annexin V and caspase 3/7. Both drugs enhanced doxorubicin-induced cytotoxicity; however, hypoxanthine showed no effect. These results indicate that theophylline is similar to caffeine; both drugs may enhance doxorubicin-induced cytotoxicity by inhibiting ATM/ATR kinases. Our data suggest that caffeine and theophylline have anticancer effects and can improve the treatment effect in canine hemangiosarcoma patients.
Lack of modification of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) rat hepatocarcinogenesis by caffeine, a CYP1A2 inducer, points to complex counteracting influences
2006, Cancer Letters
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), one of the most abundant carcinogenic heterocyclic amines in cooked foods, is speculated to be a human liver carcinogen. To test the hypothesis that it is metabolically activated by CYP1A2, we here investigated the effects of caffeine as a CYP1A2 inducer on MeIQx induced rat hepatocarcinogenesis in a medium-term liver bioassay system. Unexpectedly, no modifying effects of caffeine on MeIQx-induced hepatocarcinogenesis were evident, although up-regulation of CYP1A2 and NAT2 were detected. Therefore, mRNAs extracted from GST-P positive foci and the surrounding liver tissue in each group were analyzed to explore mechanisms in detail. The results suggest that suppression of syndecan-2 (Sdc2) and induction of cell cycle arrest through a p21-dependent pathway might have counter-acted any promotion effects of up-regulation of CYP1A2.
Mechanistic approach of contrasting modifying effects of caffeine on carcinogenesis in the rat colon and mammary gland induced with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
2003, Cancer Letters
Caffeine exerts potent chemopreventive action against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced rat mammary gland carcinogenesis, but acts as a co-carcinogen in the colon. The present work was performed to clarify mechanisms underling these organ dependent actions. Female F344 rats were given PhIP and caffeine, PhIP alone, caffeine alone or no treatment for 4 weeks. PhIP-DNA adduct formation in the colon was significantly higher in the PhIP+caffeine than in the PhIP group, but levels in the mammary glands showed no inter-group differences. CYP1A2 mRNA expression in the livers of the PhIP+caffeine group tended to be higher than in either the PhIP or the caffeine alone groups. High mRNA expression for both N-acetyltransferase (NAT) 1 and NAT2 was observed in the colon, with less expression in the mammary gland. The levels of four DNA-repair enzymes were not influenced by the caffeine treatment. In conclusion, only increased level of DNA adducts in the colon partially related to the modifying effects of caffeine on PhIP-induced rat carcinogenesis. Thus, other unknown factors must be contributory.
Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols
2002, Food and Chemical Toxicology
The beverage tea, from the top leaves of the plant Camellia sinensis is one of the most widely used beverages in the world, second only to water. Black and green tea have mostly similar actions. The active components are polyphenols, mainly epigallocatechin gallate in green tea, and the tea leaf polyphenol oxidase mediated oxidation to oolong and black tea, yielding other polyphenols, theaflavin and thearubigins. There is 40−50 mg caffeine in a 160-ml cup of tea. The chemopreventive effects of tea depend on: (1) its action as an antioxidant; (2) the specific induction of detoxifying enzymes; (3) its molecular regulatory functions on cellular growth, development and apoptosis; and (4) a selective improvement in the function of the intestinal bacterial flora. The oxidation of LDL cholesterol, associated with a risk for atherosclerosis and heart disease, is inhibited by tea. Many of cancers are caused by lifestyle elements. One is cigarette and tobacco use, leading to cancer in the oral cavity, esophagus and lung, inhibited by tea. Mice administered a tobacco nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), developed significantly fewer lung tumors than controls when given green tea or its major polyphenol, epigallocatechin gallate (EGCG). Tea suppressed the formation of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, in the lung DNA of mice given NNK. Gastric cancer, caused by a combination of Helicobacter pylori and salted foods, is lower in tea drinkers. Western nutritionally-linked cancers of the breast, colon, prostate and pancreas can be inhibited by tea. The formation of genotoxic carcinogens for these target organs during the cooking of meats, heterocyclic amines, and their effects were decreased by tea. Tea inhibited the formation of reactive oxygen species and radicals and induced cytochromes P450 1A1, 1A2 and 2B1, and glucuronosyl transferase. The higher formation of glucuronides represents an important mechanism in detoxification. The developmental aspects and growth of cancers through promotion are decreased by tea. The regular use of a widely available, tasty, inexpensive beverage, tea, has displayed valuable preventive properties in chronic human diseases.
Hepatocarcinogenesis inhibition by caffeine in ACI rats treated with 2-acetylaminofluorene
2001, Food and Chemical Toxicology
The inhibitory effects of caffeine have been demonstrated on the development of various organs in animals. The purpose of the present study was to examine the inhibitory effect of caffeine on hepatocarcinogenesis and to determine the responsive dose of caffeine on hepatocarcinogenesis in young male ACI rats. Animals given a diet containing 2-acetylaminofluorene (2-AAF) for 12 weeks and then a basal diet and tap water containing caffeine for 18 weeks showed statistically significant decreases in the incidence, multiplicity (the number of hepatic tumors per rat) and histological grade compared with rats fed a diet containing carcinogen for 12 weeks followed by tap water alone. Dose-dependent inhibition of hepatocarcinogenesis by caffeine was also seen. The inhibitory effect of caffeine on hepatocarcinogenesis in rats was found when caffeine was administered during the initiation phase.

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Food and Chemical Toxicology

Abstract

References (23)

Effects of sodium selenite and caffeine on mutagenesis induced by N-methyl-N-nitrosourea, N-methyl-N′-nitro-N-nitrosoguanidine and aflatoxin B₁ in S. typhimurium

Mutation Research

In vivo and in vitro effects of caffeine on hepatic mixed-function oxidases in rodents and chicks

Food and Chemical Toxicology

Caffeine and other phosphodiesterase inhibitors are potent inhibitors of the promotional effect of TPA on morphological transformation of hamster embryo cells

Cancer Letters

Antioxidant behaviour of caffeine: efficient scavenging of hydroxyl radicals

Food and Chemical Toxicology

Inhibition by caffeine of ovarian hormone induced mammary gland tumorigenesis in female GR mice

Cancer Letters

Total calories, body weight, and tumor incidence in mice

Cancer Research

Accumulation of abnormally high ploid nuclei in the liver of LEC rats developing spontaneous hepatitis

Japanese Journal of Cancer Research

Diet and risk of gastric cancer: a population-based case-control study in Sweden

International Journal of Cancer

Suppressive effect of caffeine on the development of hepatic tumors induced by 2-acetylaminofluorene in ACI rats

Japanese Journal of Cancer Research

Induction of hepatic ornithine decarboxylase by intraperitoneal administration of caffeine in rats

Carcinogenesis

The correlation of body weight growth with diethylnitrosamine-induced hepatocarcinogenesis in relation to serum insulin and somatomedin-C

Carcinogenesis

Cited by (35)

Drinking for protection? Epidemiological and experimental evidence on the beneficial effects of coffee or major coffee compounds against gastrointestinal and liver carcinogenesis

Evaluation of anticancer effects and enhanced doxorubicin cytotoxicity of xanthine derivatives using canine hemangiosarcoma cell lines

Lack of modification of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) rat hepatocarcinogenesis by caffeine, a CYP1A2 inducer, points to complex counteracting influences

Mechanistic approach of contrasting modifying effects of caffeine on carcinogenesis in the rat colon and mammary gland induced with 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols

Hepatocarcinogenesis inhibition by caffeine in ACI rats treated with 2-acetylaminofluorene

Research sectionEffects of caffeine on glandular stomach carcinogenesis induced in rats by N-methyl-N′-nitro-N-nitrosoguanidine and sodium chloride

Abstract

Mutation Research

Food and Chemical Toxicology

Cancer Letters

Food and Chemical Toxicology

Cancer Letters

Total calories, body weight, and tumor incidence in mice

Cancer Research

Accumulation of abnormally high ploid nuclei in the liver of LEC rats developing spontaneous hepatitis

Japanese Journal of Cancer Research

Diet and risk of gastric cancer: a population-based case-control study in Sweden

International Journal of Cancer

Suppressive effect of caffeine on the development of hepatic tumors induced by 2-acetylaminofluorene in ACI rats

Japanese Journal of Cancer Research

Induction of hepatic ornithine decarboxylase by intraperitoneal administration of caffeine in rats

Carcinogenesis

The correlation of body weight growth with diethylnitrosamine-induced hepatocarcinogenesis in relation to serum insulin and somatomedin-C

Carcinogenesis

Research section
Effects of caffeine on glandular stomach carcinogenesis induced in rats by N-methyl-N′-nitro-N-nitrosoguanidine and sodium chloride