Ki-Hwa Yang

The Selective Cyclooxygenase-2 Inhibitor Nimesulide Prevents Helicobacter pylori-Associated Gastric Cancer Development in a Mouse Model

Purpose: Helicobacter pylori infection can lead to gastric cancer, and cyclooxygenase-2 (COX-2) is overexpressed in the stomach during H. pylori infection. Therefore, we investigated whether nonsteroidal anti-inflammatory drugs might protect against this form of cancer. Specifically, we examined the chemopreventive effect of the COX-2 inhibitor nimesulide on H. pylori-associated gastric carcinogenesis in mice. Experimental Design: C57BL/6 mice were treated with the carcinogen N-methyl-N-nitrosourea (MNU) and/or H. pylori. To determine the effect of COX-2 inhibition, nimesulide was mixed with feed pellets and administered for the duration of the experiment. All of the mice were sacrificed 50 weeks after the start of the experiment. Histopathology, immunohistochemistry, and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. In vitro experiments with the human gastric cancer cell line AGS were also performed to identify mechanisms underlying cancer chemoprevention by nimesulide. Results: Gastric tumors developed in 68.8% of mice that were given both MNU and H. pylori, whereas less than 10% developed gastric tumors when given either MNU or H. pylori alone. These findings indicate that H. pylori promotes carcinogen-induced gastric tumorigenesis. In mice treated with both MNU and H. pylori, nimesulide administration substantially reduced H. pylori-associated gastric tumorigenesis, whereas substantial inductions of apoptosis were observed. In vitro studies demonstrated that nimesulide and H. pylori when combined acted synergistically to induce more apoptosis than either alone. Conclusions: Our data show that nimesulide prevents H. pylori-associated gastric carcinogenesis, and suggest that COX-2 may be a target for chemoprevention of gastric cancer.

Chemoprevention of colon cancer by Korean food plant components

Inducible cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS/NOS-2) play pivotal roles as mediators of inflammation involved in early steps of carcinogenesis in certain organs. Therefore, chemoprevention is theoretically possible through inhibition of COX-2 and/or iNOS. In the present study, we examined the chemopreventive effects of indole-3-carbinol (I3C), a constituent of cruciferous vegetables (the family of Cruciferae) such as cabbages, cauliflowers and broccoli on the multiple intestinal neoplasia (Min) genetic mouse model, and on mouse colon carcinogenesis induced by azoxymethane (AOM). The consumption of cruciferous vegetables such as cabbage, broccoli, and Brussels sprouts has been shown to have cancer chemopreventive effects in humans and experimental animals. I3C has been shown to exert a cancer chemopreventive influence in liver, colon, and mammary tissue when given before or concurrent with exposure to a carcinogen. Powdered AIN-76A diets (Harlan Teklad Research Diet, Madison, USA) containing 100 or 300 ppm I3C (group 1 or 2) or the same pellet diets without supplement (group 3) were fed to 6-week-old male C57BL/6J-Apc(Min)(/+) (Min/+) mice (The Jackson Laboratory, Bar Harbor, ME, USA) for 10 weeks. In addition the same diets were given to wild-type normal C57BL/6J-Apc(Min)(/+) littermates after AOM initiation (groups 4-7: 10 mice in each group) for 32 weeks from week 4. At 16 weeks of age, all Min/+ mice (groups 1-3) were sacrificed for assessment of intestinal polyp development. The incidences of the colonic adenomatous polyps in the groups 1-3 were 60% (12/20), 60% (15/25) and 84% (21/25), respectively. A decreasing tendency in multiplicities of the colonic adenomatous polyps in group 1 (I3C 100 ppm; 0.85 +/- 0.22; 61%) and group 2 (I3C 300 ppm; 1.32 +/- 0.28; 94%) was observed when compared with group 3 (control; 1.40 +/- 0.21; 100%). Total number of aberrant crypt foci (ACF)/colon or aberrant crypts (AC)/colon in wild-type mice of group 4 or 5 were decreased significantly compared with those of the AOM alone group (group 6) (P < 0.01). These results suggest that I3C may be a potential chemopreventive agent for colon cancer.

Silica induces nuclear factor-κB activation through TAK1 and NIK in Rat2 cell line

Silica has been known to be a factor in acute cell injury and chronic pulmonary fibrosis. In Rat2 fibroblasts, silica induced the activation of nuclear factor-kappa B (NF-kappaB), which plays a crucial role in regulating the expression of many genes involved in the subsequent inflammatory response. In addition, we observed that transforming growth factor-beta activated kinase 1 (TAK1) and NF-kappaB-inducing kinase (NIK) were involved in silica-mediated NF-kappaB activation in Rat2 cells. The dominant negative mutant forms of TAK1 and NIK inhibited the silica-induced NF-kappaB activation in Rat2 cells. Furthermore, we demonstrated that endogenous TAK1 is phosphorylated in silica-stimulated Rat2 cells. These results indicate that TAK1 functions as a critical mediator in the silica-induced signaling pathway.

Genetic polymorphisms of CYP1A1 in a Korean population

Genetic polymorphisms in the coding exons of the CYP1A1 gene were analyzed in 100 Koreans. Three types of CYP1A1 polymorphisms, specifically G134A, G184C and A2455G, were identified with allelic frequencies of 18, 3, and 16%, respectively, and no linkage was observed among them. The novel G184C polymorphism identified in this study was associated with the mutation of an alanine residue at position 62 to proline. Other earlier-reported polymorphisms in the coding region of CYP1A1 were not detected.

Health Risk Assessment of Lead in the Republic of Korea

The purpose of this study was to estimate the daily exposure to lead due to food ingestion, air inhalation, and soil ingestion in the Republic of Koreas general population, and to evaluate the level of risk associated with the current lead exposure level using the proportional daily dose (3–4 μg/kg body weight/day) corresponding to the Provisional Tolerable Weekly Intake (PTWI) suggested by the Joint FAO/WHO Expert Committee on Food Additives as the toxicological tolerance level. The estimation of the daily exposure to lead via three pathways including food, soil ingestion and air inhalation was conducted as a chronic exposure assessment. For the lead exposure assessment through dietary intake, 1,389 lead residue data for 45 commodities investigated by the Korea Food and Drug Administration during the period 1995–2000 were utilized (KFDA 1996, 1997, 1998). Six hundred seventy-two air monitoring data from 7 major cities during the period 1993–2000 and 4,500 soil residue data at 1,500 sites during the period 1999–2001 were considered for the lead exposure assessment involving air inhalation and soil ingestion, respectively. The total daily exposure to lead was estimated by combining dietary intake, inhaled amount and soil intake corresponding to the typical activity of the general population, which was treated as a group of adults with a body weight of 60 kg. For risk characterization, the daily exposure to lead was compared with the toxicological tolerance level. The level of risk due to lead exposure was calculated using the hazard ratio (HR). The dietary intake of lead was 9.71 × 10−4 mg/kg/day and the total daily exposure level, including air inhalation and soil ingestion, was 9.97 × 10−4 mg/kg/day. The exposure contributions of foods, air and soil induced from the percentage of each media to the total daily exposure were 97.4%, 2.1% and 0.5%, respectively. Of the different commodity groups, the highest contribution to the total exposure came from grain, which represented 47.7% of the total. Additional exposure to lead occurs in certain population groups due to the use of tobacco, alcoholic beverages, and the intake of other foods, all factors not considered in this study. Through the comparison of the daily exposure to lead with the tolerance level based on the PTWI, the hazard ratio was estimated as being 0.25–0.33. This value implies that no increase in blood lead level is to be expected in the general population at the current lead exposure levels.