Effect of diallyl sulfide on MNNG-induced nuclear aberrations and ornithine decarboxylase activity in the glandular stomach mucosa of the Wistar rat

In previous investigations using models for gastrointestinal cancer, the anticarcinogenic effects of diallyl sulfide (DAS), an organosulfur compound present in garlic, was established. In this study, we conducted experiments to determine whether DAS modulates two biomarkers, nuclear aberrations (NA) and ornithine decarboxylase (ODC) activity, in the glandular stomach mucosa of the Wistar rat. N-methyl-N'-nitro-N-nitrosoguanidine (MN-NG) induced dose-related NA and ODC activity in the glandular stomach 24 h and 6 h, respectively, after oral intubation with the carcinogen. Either oral or parenteral pretreatment with DAS significantly reduced the MNNG induction of NA or ODC. Furthermore, the suppressions were observed to be dose dependent. These data suggest that DAS may potentially inhibit MNNG-induced gastric cancer. In view of recent epidemiologic evidence linking reduced risk for gastric cancer with increased consumption of allium vegetables, it is clear that DAS has pluripotent effects as an anticarcinogen, although studies addressing a mechanism of action have yet to be reported.     

Combination of S-allylcysteine and lycopene induces apoptosis by modulating Bcl-2, Bax, Bim and caspases during experimental gastric carcinogenesis.

Combination chemoprevention by diet-derived agents that induce apoptosis is a promising strategy to control gastric cancer, the second most common malignancy worldwide. The present study was undertaken to investigate the apoptosis-inducing potential of a combination of S-allylcysteine (SAC), an organosulphur constituent of garlic and lycopene, a tomato carotenoid during N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) and saturated sodium chloride (S-NaCl)-induced gastric carcinogenesis in Wistar rats using the apoptosis-associated proteins Bcl-2, Bax, Bim, caspase 8 and caspase 3 as markers. Animals administered MNNG followed by S-NaCl developed squamous cell carcinomas of the stomach associated with increased Bcl-2 expression and decreased expression of Bax, Bim, caspase 8 and caspase 3. Although SAC and lycopene alone significantly suppressed the development of gastric cancer, administration of SAC and lycopene in combination was more effective in inhibiting MNNG-induced stomach tumours and modulating the expression of apoptosis-associated proteins. Our results suggest that induction of apoptosis by SAC and lycopene combination represents one of the possible mechanisms that could account for their synergistic chemopreventive activity against gastric cancer.     

Rosiglitazone suppresses gastric carcinogenesis by up-regulating HCaRG expression

Our previous study demonstrated that PPARgamma ligand rosiglitazone prevents gastric carcinogenesis in rats induced by chemical carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). In this study, we attempted to identify novel anti-cancer mechanisms of rosiglitazone. By examining the gene expression profiles of MNNG-induced and rosiglitazone-treated gastric cancer with Uniset Rat I Bioarray microarray, we identified a gene that showed prominent responses in the rosiglitazone-treated group. The hypertension-related, calcium-regulated gene (HCaRG) was significantly up-regulated in rat gastric carcinoma of the rosiglitazone-treated group when compared with the MNNG group. We further examined HCaRG expression in human gastric cancer and found that the expression of HCaRG was down-regulated in human gastric cancerous tissue. Rosiglitazone markedly induced the expression of HCaRG in the AGS cell line. The up-regulation of HCaRG may be one of the mechanisms underlying the chemopreventive effect of rosiglitazone in gastric cancer.     

大蒜对MNNG诱发实验性胃癌及癌前病变过程中血Tch,LDL,HDL的影响

在ＭＮＮＧ诱发大鼠胃腺癌及癌前病变的过程中，观察了血Ｔｃｈ、ＬＤＬ、ＨＤＬ的变化及大蒜对其的影响。结果显示：ＭＮＮＧ组血Ｔｃｈ与ＬＤＬ低于正常对照组，ＨＤＬ高于对照组，具有显著性差异，证明实验性胃癌及癌前病变伴有低Ｔｃｈ、ＬＤＬ血症和高ＨＤＬ血症。预防组和治疗组血Ｔｃｈ、ＬＤＬ、ＨＤＬ与对照组无显著性差异。与ＭＮＮＧ组比较，预防组Ｔｃｈ、ＬＤＬ略高，ＨＤＬ略低，但无显著性；治疗组Ｔｃｈ、ＬＤＬ高于ＭＮＮＧ组，有非常显著性意义，而ＨＤＬ相近，无显著性。提示大蒜对ＭＮＮＧ诱发实验性胃癌具有抑制与逆转作用。     

Diallyl sulfide inhibits diethylstilbestrol-induced lipid peroxidation in breast tissue of female ACI rats: implications in breast cancer prevention

Diallyl sulfide (DAS) is a component of garlic and prevents cancer in several animal models in various organs. The chemopreventive effects of DAS are attributed to modulation of enzymes to alter the bioactivation of xenobiotics. Diethylstilbestrol (DES) is a synthetic estrogen that causes breast cancer in female ACI rats subsequent to metabolism with concurrent free radical production. This study assessed the effect of DAS on DES-induced reactive oxygen species (ROS) using lipid peroxidation as an empirical endpoint. We have demonstrated that acute exposure to DES results in a significant increase in lipid hydroperoxides (LPH) in breast tissue and DAS attenuated DES-induced LPH concentrations. Two-week exposure to DES caused significant increases in LPH concentrations in breast and liver tissues. DES-induced LPH concentrations were decreased by coadministration of DAS at this time point. There were no statistical differences in the concentrations of LPH in breast and liver tissues of rats treated for 4/6 weeks with DAS/DES. These results demonstrate that DAS inhibits the production of ROS which suggests that DAS effectively inhibits DES bioactivation in female ACI rats which may have implications for chemopreventive intervention strategies. Our results suggest that garlic consumption might be useful for the prevention of human breast cancers.     

Attenuating effect of ornithine decarboxylase inhibitor (1,3-diaminopropane) on bombesin enhancement of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine.

The effects of combined administration of bombesin and the ornithine decarboxylase (ODC) inhibitor 1,3-diaminopropane (DAP) on the incidence and number of gastric tumors induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the ODC activity of the gastric wall and the labelling index of the gastric mucosa were investigated in inbred Wistar rats. Rats were given drinking water containing MNNG (50 micrograms/ml) for 25 weeks and then drinking water containing DAP (2.5 g/l) and/or injections of 40 micrograms/kg body weight of bombesin in depot form every other day. Administration of bombesin alone resulted in significant increases in the incidence of gastric cancers, the ODC activity of the antral portion of the gastric wall and the labelling index of the antral mucosa. Administration of DAP with bombesin significantly reduced enhancement by the latter of gastric carcinogenesis, ODC activity of the antral portion of the gastric wall and the labelling index of the antral mucosa. Our results suggest that ODC inhibition attenuated the enhancement of gastric carcinogenesis by bombesin, and that this enhancement by bombesin was mediated by polyamine biosynthesis.     

Ornithine decarboxylase inhibitor attenuates NaCl enhancement of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine

The effects of combined administration of NaCl and the ornithinedecarboxylase (ODC) inhibitor 1,3-diaminopropane (DAP) on theincidence and number of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) and on the ODC activity of the gastric wall and the labelingindex of the gastric mucosa were investigated in inbred Wistarrats. Rats were given drinking water with or without 2.5 g/1DAP and chow pellets with and without 10% NaCl ad libitum after25 weeks of oral administration of MNNG. At week 52 feeding10% NaCl resulted in significant increases in the incidenceof gastric cancers, in the ODC activity of the antral portionof the gastric wall and in the labeling index of antral epithelialcells. Administration of both NaCl and DAP significantly reducedthe enhancements by NaCl of gastric carcinogenesis, ODC activityof the antral wall and the labeling index of antral epithelialcells. These results suggest that inhibition of ODC attenuatesNaCl enhancement of gastric carcinogenesis and that enhancementby NaCl of gastric carcinogenesis is mediated by polyamine biosynthesis.     

大蒜对N—亚硝酰胺致突变作用的影响

大蒜摄入量与患胃癌的风险呈负相关,可能具有防胃癌作用。我们使用Ames试验探讨了大蒜对人胃癌可疑病因N-亚硝酰胺致突变性的影响。结果表明大蒜球茎匀浆在无毒性的剂量(5-15mg/皿)范围内有阻断100nmol/皿ENNG (N-ethyl-N′-nitro-N-nitrosoguanidine)、150nmol/皿的MNU(N-methyl-N-nitrosourea)和200μl/皿亚硝化鱼露直接致TA100回复突变作用,但在平板掺入试验中增强5nmol/皿MNNG(N-methyl-N′-nitro-N-nitrosoguanidine)致突变强度,在预培养试验中则抑制它的致突变作用。大蒜的有效成分大蒜素(0.1-0.3μmol/皿)能明显地阻断TA100的致突变性。以上结果证明大蒜及其有效成分有抗N-亚硝酰胺致突变的作用。文中对大蒜在特殊条件下促进MNNG致突变的机理进行了讨论。     

Depleted dopamine in gastric cancer tissues: dopamine treatment retards growth of gastric cancer by inhibiting angiogenesis.

PURPOSE: It has been recently shown that the catecholamine neurotransmitter dopamine (DA) strongly and selectively inhibits vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-induced angiogenesis. Gastric cancer is highly angiogenic and is dependent on VEGF for its growth and progression. Because substantial amounts of DA present in normal stomach tissues has been implicated in several gastric functions, we therefore investigated the role, if any, of this neurotransmitter in the growth and progression of gastric cancer. EXPERIMENTAL DESIGN: Initially, the status of DA and tyrosine hydroxylase, the rate-limiting enzyme required for DA synthesis, were determined in human gastric cancer tissues and in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer tissues of rats. On the basis of our observation of inverse correlation between stomach DA and gastric cancer growth, we determined the effect of pharmacological dose of DA on the angiogenesis and growth of MNNG induced gastric cancer in rats and Hs746T human gastric cancer in nude mice. RESULTS: DA and tyrosine hydroxylase were absent in both human and rat gastric cancer tissues. On the contrary, a low nontoxic pharmacological dose of DA significantly retarded tumor angiogenesis by inhibiting VEGFR-2 phosphorylation in tumor endothelial cells, which expressed DA D(2) receptors. This action of DA was associated with the growth inhibition of both MNNG-induced rat malignant gastric tumors and xenotransplanted human gastric cancer in nude mice. CONCLUSIONS: Our study demonstrates that there is an inverse correlation between endogenous stomach DA and gastric cancer and indicates that DA already in clinical use for other purposes might have a role as an antiangiogenic agent in the treatment of gastric cancer.