Article

Chemoprevention of gastric cancer by celecoxib in rats

February 2004
Gut 53(2):195-200

February 2004
53(2):195-200

DOI:10.1136/gut.2003.021477

Source
PubMed

Authors:

Jun Yu

The Chinese University of Hong Kong

Zhirong Zeng

Sun Yat-Sen University of Medical Sciences

Wai K Leung

The University of Hong Kong

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Overexpression of cyclooxygenase 2 (COX-2) is frequently detected in gastric cancer and is believed to play a crucial role in gastric carcinogenesis. Aim: We examined the chemopreventive effect of a COX-2 inhibitor in an animal model of stomach carcinogenesis. Eighty six male Wistar rats were divided into six different treatment groups: group A, water alone (n = 5); group B, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG 100 micro g/ml) (n = 16); group C, indomethacin (3 mg/kg/day) (n = 16); group D, celecoxib (5 mg/kg/day) (n = 17); group E, celecoxib (10 mg/kg/day) (n = 16); and group F, celecoxib (20 mg/kg/day) (n = 16). Group B-F animals were treated with 10% sodium chloride (in the initial six weeks) and MNNG in drinking water to induce adenocarcinoma in the stomach. All animals received treatment for 40 weeks, and were sacrificed after death or at 48 weeks. Gastric neoplasm was evaluated by histology. The incidences of gastric cancer were 0% in group A, 75% in group B, 68.8% in group C, 70.6% in group D, 18.8% in group E, and 31.3% in group F (p = 0.002, ANOVA). Compared with MNNG controls, treatment with celecoxib 10 mg/kg/day also showed lower tumour multiplicity (0.19 (0.40) v 1.00 (0.73); p = 0.004) and lower mean tumour volume (2.4 v 2805 mm(3); p = 0.02). Although tumours had significantly higher COX-2 expression than their adjacent normal tissues (p<0.02), there was no significant difference in COX-2 levels among tumours in the different treatment groups. The lowest tumour prostaglandin E(2) level was found in the indomethacin treated group, suggesting that the chemopreventive effect of celecoxib may be mediated by a COX independent pathway. While treatment with indomethacin had no significant effect on tumour development, treatment with celecoxib reduced gastric cancer incidence and growth in rats.

Leptin enhances N-methyl-N’-nitro-N-nitrosoguanidine (MNNG)-induced tumour growth in gastric mucosa of male Sprague-Dawley rats

Article

Full-text available

Dec 2019
MOL BIOL REP

Individuals who are obese are at a greater risk of developing gastric cancer. They are however also hyperleptinaemic. Chronic leptin treatment has been shown to upregulate numerous cancer-causing genes in the stomach of male Sprague-Dawley rats. It is however unclear if leptin enhances the effect of gastric carcinogens in vivo. This study was therefore done to investigate the effect of leptin on gastric carcinogenesis in rats treated with N-methyl-N’-nitro-N-nitrosoguanidine (MNNG). Twenty-four, 6-week old male Sprague-Dawley rats were divided equally into three groups: G1 served as age-matched controls; G2 was treated with MNNG in drinking water ad libitum (200 mg L⁻¹); G3 was given leptin and MNNG. Rats were euthanized after 40 weeks of treatment and their stomachs were removed for histopathology, microarray, and RT-qPCR analysis. Fisher’s exact test and one-way ANOVA were used to analyse the data. Fifty percent of the MNNG-treated rats developed gastric hyperplasia (p < 0.05), but there was no significant change in any carcinogenic genes. Concurrent MNNG and leptin treatment however induced hyperplasia, dysplasia, hypertrophy, and adenocarcinoma in 75% (6/8) of the rats; with upregulation of microRNAs, olfactory receptors, Hey2 (transcription factor), Tmed2 (vesicular trafficking), and Lcn11 (cell proliferation) genes. It appears that leptin enhances MNNG- induced tumour growth in stomachs of Sprague-Dawley rats and its role in gastric cancer requires further scrutiny.

Preliminary evaluation of anticancer efficacy of pioglitazone combined with celecoxib for the treatment of non-small cell lung cancer

Article

Full-text available

Feb 2022
INVEST NEW DRUG

Purpose: Among the lung cancer types, non-small cell lung cancer (NSCLC) is prominent and less responsive to chemotherapy. The current chemotherapeutics for NSCLC are associated with several dose-limiting side effects like bone-marrow suppression, neurotoxicity, nephrotoxicity, and ototoxicity, etc. which are causing non-compliance in patients. Many tumors, including breasts, lung, ovarian, etc. overexpress PPAR-γ receptors and COX-2 enzymes, which play a crucial role in tumor progression, angiogenesis, and metastasis. Lack of PPAR-γ activation and overproduction of prostaglandins, result in uncontrolled activation of Ras/Raf/Mek ultimately, NF-κB mediated tumor proliferation. This study aimed to investigate the anti-cancer potential of PPAR-γ agonist Pioglitazone combined with COX-2 inhibitor Celelcoxib in NSCLC. Methods: Sixty adult Balb/C male mice were classified into sham control, disease control, and treatment groups. Mice were treated with Nicotine-derived nitrosamine ketone (NNK) (10 mg/kg), pioglitazone (10 & 20 mg/kg) and celecoxib (25 & 50 mg/kg). Weekly body weight, food intake, mean survival time & % increased life span were determined. Tumor weight and histopathological analysis were performed at the end of the study. Results: The significant tumor reducing potential of pioglitazone combined with celecoxib was observed (p < 0.05). The treatment groups (treated with pioglitazone and celecoxib) showed a remarkable decrease in lung tumor weight, improved life span and mean survival time (p < 0.05). Histopathological studies confirm that treatment groups (treated with pioglitazone and celecoxib) reframed the lung architecture compared to disease control. Conclusion: Preliminary results revealed that pioglitazone adjunacy with celecoxib may be an effective chemo-preventive agent against NNK induce NSCLC.

Prostaglandin E 2 induces DNA hypermethylation in gastric cancer in vitro and in vivo

Article

Full-text available

Aug 2019
thno

Rationale: Prostaglandin E2 (PGE2) is a pro-inflammatory eicosanoid up-regulated in gastric cancer (GC). However, its impact on epigenetic dysfunction in the process of gastric carcinogenesis is unknown. In this study, we investigate the role of PGE2 in DNA methylation in gastric epithelium in vitro, in mice, and humans. Methods: PGE2-induced DNMT3B and DNA methylation was determined in gastric cell lines and COX-2 transgenic mice. Effect of COX-2 inhibition on DNA methylation was evaluated in a randomized controlled trial. Efficacy of combined COX-2/PGE2 and DNMT inhibition on GC growth was examined in cell lines and mice models. Results: PCR array analysis of PGE2-treated GC cells revealed the up-regulation of DNMT3B, a de novo DNA methyltransferase. In GC cells, PGE2 induced DNMT3B expression and activity, leading to increased methylated cytosine (5mC) and promoter methylation of tumor suppressive genes (MGMT and CNR1). Consistently, Cox-2 (rate-limiting enzyme for PGE2 biosynthesis) transgenic expression in mice significantly induced Dnmt3b expression, increased 5mC content, and promoted Mgmt promoter methylation. We retrospectively analyzed the 5mC content of 42 patients with intestinal metaplasia (a precancerous lesion of GC) treated with a COX-2 specific inhibitor Rofecoxib or placebo for 2 years, revealing that the COX-2 inhibitor significantly down-regulated 5mC levels (N=42, P=0.009). Collectively, these data indicate that PGE2 is closely related to DNA hypermethylation in vitro and in vivo. Using genome-wide 450K methylation array, we identified chromosomal genes (POT1, ATM and HIST1H2AA) were preferentially methylated by PGE2. Biofunctional work revealed that POT1 functions as a tumor suppressor. Finally, we demonstrated that combinatorial inhibition of COX-2 and DNMT using Celecoxib and Decitabine synergistically inhibited GC growth in vitro and in vivo. Conclusion: This study suggested that PGE2 promotes DNA methylation in GC, and that co-targeting of PGE2 and DNMT inhibits GC.

Efficacy and safety of combined low doses of either diclofenac or celecoxib with gabapentin versus their single high dose in treatment of neuropathic pain in rats

Article

Feb 2018

Neuropathic pain is a worldwide health problem with no consensus regarding its optimal therapy. This study compared the analgesic effect and gastric, hepatic, and renal safety of combined low doses of diclofenac and celecoxib with gabapentin versus their individual high doses in the treatment of neuropathic pain in rats. Left sciatic nerve ligation was used as neuropathic pain model. Rats were allocated into 7 groups (7 rats for each): sham control; model group (received vehicle); Gaba-group (received gabapentin (100 mg/kg /day); Diclo 10-group (received diclofenac (10 mg/kg); Cele 10-group (received celecoxib (10 mg/kg/day); Gaba + Diclo 5 (receivedgabapentin(100 mg/kg /day) plus diclofenac (5 mg/kg); Gaba + Cele 5 (received gabapentin (100 mg/kg/day) plus celecoxib (5 mg/kg)). The analgesic effect was assessed using both hot plate and acetone tests. The impact of the used drugs on peptic ulcer index, liver enzymes, and serum urea and creatinine was evaluated, along with histopathological examination and oxidative stress parameters. Combination therapy of low dose of either diclofenac or celecoxib, with gabapentin showed higher analgesic effect compared with their individual high doses as indicated by prolonged response time in hot plate test and decreased frequency of paw withdrawal in acetone test. Their effect was associated with gentle effect on gastric mucosa, renal and hepatic integrity and oxidative stress parameters. In conclusion, the use of combined low doses of either diclofenac or celecoxib with gabapentin is better than high dose monotherapy regarding both the efficacy and safety.

Anti-cancer effect of low dose of celecoxib may be associated with lnc-SCD-1:13 and lnc-PTMS-1:3 but not COX-2 in NCI-N87 cells

Article

Jun 2017

In order to investigate the mechanism of celecoxib and whether long non-coding RNAs (lncRNAs) were involved in the effects of celecoxib treatment in NCI-N87 cells, NCI-N87 cells were treated with 15, 30 and 60 μM celecoxib and an MTT assay was performed to assess cell viability. Following treatment with 15 μM celecoxib, the cell cycle and apoptosis were analyzed by flow cytometry, and the mRNA levels of lnc-SCD-1:13, lnc-PTMS-1:3, cyclooxygenase-2 (COX-2), integrin α3 (ITGA3) and DSH homolog 1 (DVL1) were detected by reverse transcription quantitative PCR (RT-qPCR) in NCI-N87 cells. MTT analysis demonstrated that celecoxib significantly inhibited cell viability in treated cells compared with untreated cells. Flow cytometry analysis revealed that, compared with untreated cells, the percentage of cells in the G0/G1 phase was significantly increased, and the percentage of cells in the S and G2 phase was decreased. In addition, the percentage of early and late apoptotic cells was increased in cells treated with 15 μM celecoxib compared with the control. RT-qPCR analysis also demonstrated that the mRNA levels of lnc-SCD-1:13, lnc-PTMS-1:3, ITGA3 and DVL1 were increased following treatment with celecoxib (15 μM; P<0.05). However, there were no significant differences in the expression of COX-2 mRNA between cells treated with celecoxib (15 μM) and untreated cells. The present study demonstrated that a low dose of celecoxib may be involved in regulating cell growth independent of COX-2 in NCI-N87 cells. Furthermore, ITGA3 and/or DVL1 co-expressed with lnc-SCD-1:13 and lnc-PTMS-1:3 may be associated with the effects of treatment with a low dose of celecoxib in NCI-N87 cells.

Anti-LeY antibody enhances therapeutic efficacy of celecoxib against gastric cancer by downregulation of MAPKs/COX-2 signaling pathway: correlation with clinical study

Article

Full-text available

Dec 2014

Helicobacter pylori (H. pylori) is a major causative agent for the induction of chronic gastritis, gastric ulcer and gastric cancer. Celecoxib (COX-2 inhibitor) inhibits gastric cancer cell proliferation, but with low treatment efficacy, limiting its applications. It is important to develop a better strategy to improve the efficacy of celecoxib. Lewis Y (LeY) is a difucosylated oligosaccharide, highly expressed in 60-90 % of human epithelial cancers, including gastric cancer. We previously found that H. pylori infection was associated with high level of LeY in gastric cancer. Herein, we analyzed the correlation between H. pylori and cyclo-oxygenase-2 (COX-2), LeY, gastric markers (CA724 and GRN) in gastric patient's tissue and serum samples by IHC and ELISA. Furthermore, we treated the primary gastric cancer cells with celecoxib, anti-LeY antibody or the combination, and analyzed their therapeutic efficacy on CA724, GRN and COX-2 expression by Western blot, flow cytometry and ELISA. We found that gastric cancer had significantly high expression of H. pylori, COX-2, CA724, and GRN compared to gastric ulcers and chronic gastritis (P < 0.0001). H. pylori level showed significant correlation with COX-2 (R-0.552), LeY (R-0.861), CA724 (R-0.714) and GRN (R-0.664) (P < 0.0001). Additionally, the combination therapy led to impressive inhibition of gastric cancer cell proliferation, with decreased expression of COX-2, CA724 and GRN through downregulation of MAPKs/COX-2 pathway (P < 0.01). Our findings suggest that anti-LeY antibody enhances the cancer cell proliferation inhibitory effects of celecoxib, which might be a new feasible way for gastric cancer therapy.

Rutaecarpine Ameliorates Murine N-Methyl-N’-Nitro-N-Nitrosoguanidine-Induced Chronic Atrophic Gastritis by Sonic Hedgehog Pathway

Article

Full-text available

Aug 2023
MOLECULES

CAG is a burdensome and progressive disease. Numerous studies have shown the effectiveness of RUT in digestive system diseases. The therapeutic effects of RUT on MNNG-induced CAG and the potential mechanisms were probed. MNNG administration was employed to establish a CAG model. The HE and ELISA methods were applied to detect the treatment effects. WB, qRT-PCR, immunohistochemistry, TUNEL, and GES-1 cell flow cytometry approaches were employed to probe the mechanisms. The CAG model was successfully established. The ELISA and HE staining data showed that the RUT treatment effects on CAG rats were reflected by the amelioration of histological damage. The qRT-PCR and WB analyses indicated that the protective effect of RUT is related to the upregulation of the SHH pathway and downregulation of the downstream of apoptosis to improve gastric cellular survival. Our data suggest that RUT induces a gastroprotective effect by upregulating the SHH signaling pathway and stimulating anti-apoptosis downstream.

The ketogenic diet could improve the efficacy of curcumin and Oldenlandia diffusa extract in the treatment of gastric cancer by increasing miR340 expression and apoptosis mediated by autophagy, oxidative stress, and angiogenesis

Article

Full-text available

Oct 2022
J FOOD BIOCHEM

The pathogenesis of gastric cancer is a multistage process that involves glucose metabolism, inflammation, oxidative damage, angiogenesis, autophagy, and apoptosis. Moreover, microRNA‐340 (miR340) also plays a vital role in tumorigenesis and the biology of gastric cancer as an epigenetic factor. It seems that the use of ketogenic diets (KDs) and plant extracts that have antitumor, anti‐inflammatory, and antioxidant properties can be good treatment options to cure gastric cancer. The aim of this study was to investigate the role of miR‐340 on pathways involved in the pathogenesis of gastric cancer and the improving effects of the KD, Oldenlandia diffusa extract (ODE), and curcumin in the animal model of gastric cancer. One hundred and ten male Wistar rats were divided into control and treatment groups. The expression of miR‐340 along with genes involved in inflammation, oxidative damage, angiogenesis, and apoptosis were assessed. The results showed that the KD and different doses of curcumin and ODE in a dose‐dependent behavior could induce apoptosis and the expression of the Akt/mTORC1 pathway and inhibit inflammation, oxidative damage, and angiogenesis in the gastric tissue of rats with cancer. In addition, there was no significant difference between cancer groups receiving ODE and curcumin. These results also showed that consumption of KD could significantly increase the efficacy of ODE and curcumin which may be due to increasing miR‐340 expression. The results of this study suggested well that the KD along with conventional therapies in traditional medicine can be a useful solution for the prevention and treatment of gastric cancer. Practical applications Gastric cancer is the third leading cause of cancer death, and genetic and epigenetic factors, including miR‐340, are involved in its pathogenesis. However, the use of ketogenic diets (KDs) and plant products such as curcumin and Oldenlandia diffusa extract (ODE) can play an effective role in inhibiting tumorigenesis in some cancers. Our results showed that the KD and different doses of curcumin and ODE could induce apoptosis and the expression of the Akt/mTORC1 pathway and inhibit inflammation, oxidative damage, and angiogenesis in the gastric tissue. Moreover, the KD could significantly increase the efficacy of ODE and curcumin which may be due to an increase in miR‐340 expression. These findings provide novel perceptions about the mechanisms of the KD, curcumin, and ODE to cure gastric cancer. It suggested that the KD as adjunctive therapy along with conventional therapies in traditional medicine could be considered a useful solution to prevent and treat gastric cancer.

Is intestinal metaplasia the point of no return in the progression of gastric carcinogenesis?

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Nov 2021
CHINESE MED J-PEKING

Overview on the Role of E-Cadherin in Gastric Cancer: Dysregulation and Clinical Implications

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Jul 2021

Gastric cancer is the fifth most common cancer and the third most common cause of cancer death all over the world. E-cadherin encoded by human CDH1 gene plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. Full-length E-cadhrin tethered on the cell membrane mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. After proteolysis, the extracellular fragment of the full-length E-cadhein is released into the extracellular environment and the blood, which is called soluble E-cadherin (sE-cadherin). sE-cadherin promots invasion and metastasis as a paracrine/autocrine signaling molecule in the progression of various types of cancer including gastric cancer. This review mainly summarizes the dysregulation of E-cadherin and the regulatory roles in the progression, invasion, metastasis, and drug-resistance, as well as its clinical applications in diagnosis, prognosis, and therapeutics of gastric cancer.

Leptin increases the expression of tumour promoter genes and decreases the expression of tumour suppressor genes in stomach of female Sprague-Dawley rats

Article

Full-text available

Mar 2021

Background: Epidemiologic studies indicate that the incidence of gastric cancer is lower in females than in males due to the protective effects of oestrogen. However, a few reports have found that there was no difference in relative risk of gastric cancer in obese females compared to obese males. Our recent studies have shown that leptin administration promotes tumour growth in the stomach of male Sprague-Dawley rats. However, it is unknown whether leptin can also equally induce gastric tumorigenesis in female rats. This study therefore examined the effects of leptin on tumour development in stomachs of female Sprague-Dawley rats. Methodology: Female Sprague-Dawley rats aged 6 weeks were divided into 2 groups; leptin group that was given daily intraperitoneal injections of leptin at a dose of 60 µg/kg for 40 weeks (n=8) and a control group that was given daily intraperitoneal injections of an equal volume of normal saline (n=8). Body weights were measured weekly. After 40 weeks, the rats were euthanised and their stomachs collected for histopathological examination and gene analysis. Nine target genes commonly involved in tumorigenesis were selected for RT-PCR, which included APC, ARID1A, E-Cadherin, FAT4, L-Myc, PGC, PPARG, TFF1, and TFF2. Data were analysed using one-way ANOVA. Results: No macroscopic or microscopic changes were found in the stomach of leptin-treated rats. However, gene analysis revealed significant decrease in tumour suppressor genes like ARID1A, E-cadherin, APC, TFF1, and PPARG, but not FAT4. Tumour promoter genes L-Myc and TFF2 were both significantly upregulated in leptin-treated rats. In situ expression of PGC, which is a negative marker for gastric cancer, was found decreased considerably as well. No significant differences in body weight were found between control and leptin-treated rats. Conclusion: The evident down regulation of some tumour suppressor genes and up-regulation of some tumour promoter genes in leptin-treated rats seem to indicate a tumorigenic potential of leptin in female rats as well, although it may not be as profound as reported in male Sprague-Dawley rats.

Modulatory effect of Tagetes erecta flowers essential oils via Nrf2/HO-1/NF-κB/p65 axis mediated suppression of N-methyl-N'nitro-N-nitroguanidine (MNNG) induced gastric cancer in rats

Article

Full-text available

Mar 2021
MOL CELL BIOCHEM

Protective effect of Tagetes erecta flowers essential oils was investigated on oxidative stress, immune response, inflammation, and apoptosis against N-methyl-Nʹnitro-N-nitroguanidine (MNNG) induced gastric cancer in rats. Essential oil were extracted from Tagetes erecta flowers and analyzed using gas chromatography–mass spectrometry (GC–MS). For observing a protective effect against MNNG induced gastric cancer, we divided rats into 4 groups (group A to D) having 10 rats in each group. Performed various experiments and measured a different parameters to investigate antioxidant activity, immune response, anti-inflammatory and anti-apoptotic activity. The levels of malondialdehyde were markedly increased in the presence of N-methyl-Nʹnitro-N-nitroguanidine, whereas, the antioxidant activities of superoxide dismutase, and catalase were lowered in the treated rats in contrast with the control. Intervention with TEEO to gastric cancer-induced rats upregulated the redox status and the activity of the immune system to decrease cancer risk. The proinflammatory cytokines (IL-6 and TNF-α) secretions that were induced by MNNG were markedly inhibited by TEEO. Administration of TEEO also significantly reduced terminal deoxynucleotidyl transferase dUTP nick end labeling positive gastric cancer cells, expression of mRNA of caspase-3, and Bax. Whereas, the expression of Bcl-2 was increased. Additionally, downregulation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and IκBα degradation and the nuclear factor-κB (NF-κB) p65 expression in tissues of the stomach of MNNG-induced-rats were markedly elevated due to TEEO. This suggested possession of TEEO with a protective shield against MNNG induced gastric cancer by the exertion of antioxidative stress, anti-apoptotic response, the anti-inflammatory response through Nrf2/HO-1, and NF-κB signaling pathways.

Effects of Plant and Animal Natural Products on Mitophagy

Article

Full-text available

Mar 2020
OXID MED CELL LONGEV

Mitophagy is a protected cellular process that is essential for autophagic removal of damaged mitochondria and for preservation of a healthy mitochondrial population. In the last years, a particular interest has been devoted in studying the effects of natural compounds on mitophagy. Different natural compounds may modulate mitochondrial oxidative phosphorylation, the production of mitochondrial reactive oxygen species, the expression of mitophagy- and autophagy-related genes, and the activities of transcription factors which regulate the expression of mitochondrial proteins, thereby controlling mitochondrial damage and mitophagy. Remarkably, since mitochondrial function has a crucial role in the pathogenesis of various diseases (e.g., cancer, atherosclerosis, Duchenne muscular dystrophy, diabetes complications, Alzheimer’s disease, and hepatic steatosis), these effects might have important therapeutic implications. In this review, preclinical studies investigating the role of different natural compounds in the modulation of mitophagy will be discussed.

Impact factors that modulate gastric cancer risk in Helicobacter pylori‐infected rodent models

Article

Apr 2019

Gastric cancer causes a large social and economic burden to humans. Helicobacter pylori (H pylori) infection is a major risk factor for distal gastric cancer. Detailed elucidation of H pylori pathogenesis is significant for the prevention and treatment of gastric cancer. Animal models of H pylori‐induced gastric cancer have provided an invaluable resource to help elucidate the mechanisms of H pylori‐induced carcinogenesis as well as the interaction between host and the bacterium. Rodent models are commonly used to study H pylori infection because H pylori‐induced pathological processes in the stomachs of rodents are similar to those in the stomachs of humans. The risk of gastric cancer in H pylori‐infected animal models is greatly dependent on host factors, bacterial determinants, environmental factors, and microbiota. However, the related mechanisms and the effects of the interactions among these impact factors on gastric carcinogenesis remain unclear. In this review, we summarize the impact factors mediating gastric cancer risk when establishing H pylori‐infected animal models. Clarifying these factors and their potential interactions will provide insights to construct animal models of gastric cancer and investigate the in‐depth mechanisms of H pylori pathogenesis, which might contribute to the management of H pylori‐associated gastric diseases.

Low-dose anti-inflammatory combinatorial therapy reduced cancer stem cell formation in patient-derived preclinical models for tumour relapse prevention

Article

Full-text available

Feb 2019

Background Emergence of drug-resistant cancer phenotypes is a challenge for anti-cancer therapy. Cancer stem cells are identified as one of the ways by which chemoresistance develops. Method We investigated the anti-inflammatory combinatorial treatment (DA) of doxorubicin and aspirin using a preclinical microfluidic model on cancer cell lines and patient-derived circulating tumour cell clusters. The model had been previously demonstrated to predict patient overall prognosis. Results We demonstrated that low-dose aspirin with a sub-optimal dose of doxorubicin for 72 h could generate higher killing efficacy and enhanced apoptosis. Seven days of DA treatment significantly reduced the proportion of cancer stem cells and colony-forming ability. DA treatment delayed the inhibition of interleukin-6 secretion, which is mediated by both COX-dependent and independent pathways. The response of patients varied due to clinical heterogeneity, with 62.5% and 64.7% of samples demonstrating higher killing efficacy or reduction in cancer stem cell (CSC) proportions after DA treatment, respectively. These results highlight the importance of using patient-derived models for drug discovery. Conclusions This preclinical proof of concept seeks to reduce the onset of CSCs generated post treatment by stressful stimuli. Our study will promote a better understanding of anti-inflammatory treatments for cancer and reduce the risk of relapse in patients.

A Ru(II)-p-cymene compound bearing naproxen-pyridineamide. Synthesis, spectroscopic studies, computational analysis and in vitro anticancer activity against lung cells compared to Ru(II)-p-cymene-naproxen and the corresponding drug ligands

Article

Feb 2019
INORG CHIM ACTA

Silymarin and celecoxib ameliorate experimental varicocele-induced pathogenesis: evidences for oxidative stress and inflammation inhibition

Article

Full-text available

Jun 2018
INT UROL NEPHROL

Background: The present study was done to investigate the ameliorative effect of silymarin (SMN) and celecoxib (CEL) on varicocele (VCL)-induced detrimental impact in testicular tissue. Methods: Mature Wistar rats were divided into control and test groups. Following VCL induction, the animals in test group were subdivided into non-treated VCL-induced, SMN-treated (50 mg/kg, orally), CEL-treated (10 mg/kg) and SMN + CEL-treated groups. Following 60 days, testicular total antioxidant capacity (TAC), malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), glutathione peroxidase (GSH-px), total thiol molecules (TTM), mRNA and protein levels of COX2 and mRNA level of iNos were analyzed. Moreover, the germinal cells apoptosis and mRNA damage were examined. Results: Observations revealed that co-administration of SMN and CEL significantly (P < 0.05) up-regulated TAC, SOD, GSH-px and TTM levels and resulted in a remarkable (P < 0.05) reduction in iNos and COX2 expression, NO and MDA contents. The animals in SMN + CEL-treated group exhibited significantly (P < 0.05) lower number of apoptotic cells and cells with mRNA damage per one mm2. Conclusion: The SMN by up-regulating testicular TAC, SOD, GSH-px and TTM levels and the CEL by inhibiting COX2 and iNos expression as well as NO content could fairly ameliorate the VCL-decreased spermatogenesis.

Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression

Article

Full-text available

Nov 2017
BRIT J CANCER

Background: We investigated the role of prostaglandin receptors (e.g. prostaglandin E2 receptor 2 (EP2), EP4) and the efficacy of celecoxib in urothelial tumourigenesis and cancer progression. Methods: We performed immunohistochemistry in bladder cancer (BC) tissue microarrays, in vitro transformation assay in a normal urothelial SVHUC line, and western blot/reverse transcription-polymerase chain reaction/cell growth assays in BC lines. Results: EP2/EP4 expression was elevated in BCs compared with non-neoplastic urothelial tissues and in BCs from those who were resistant to cisplatin-based neoadjuvant chemotherapy. Strong positivity of EP2/EP4 in non-muscle-invasive tumours or positivity of EP2/EP4 in muscle-invasive tumours strongly correlated with disease progression or disease-specific mortality, respectively. In SVHUC cells, exposure to a chemical carcinogen 3-methylcholanthrene considerably increased and decreased the expression of EP2/EP4 and phosphatase and tensin homologue (PTEN), respectively. Treatment with selective EP2/EP4 antagonist or celecoxib also resulted in prevention in 3-methylcholanthrene-induced neoplastic transformation of SVHUC cells. In BC lines, EP2/EP4 antagonists and celecoxib effectively inhibited cell viability and migration, as well as augmented PTEN expression. Furthermore, these drugs enhanced the cytotoxic activity of cisplatin in BC cells. EP2/EP4 and PTEN were also elevated and reduced, respectively, in cisplatin-resistant BC sublines. Conclusions: EP2/EP4 activation correlates with induction of urothelial cancer initiation and outgrowth, as well as chemoresistance, presumably via downregulating PTEN expression.British Journal of Cancer advance online publication, 9 November 2017; doi:10.1038/bjc.2017.393 www.bjcancer.com.

Anticancer Activity and Phenolic Compounds of Pistacia atlantica Extract

Article

Full-text available

Apr 2017

Majid Asadi-Samani

Recently a lot of studies have been conducted to identify natural compounds for prevention of the development and recurrence of cancers. The present study aimed to determine phytochemical content and anti proliferative activity of Pistacia atlantica extract. Ethanolic extract of Pistacia atlantica was prepared. The antioxidant activity, total phenol, flavonoid and flavonol content of the extract were evaluated. Cytotoxicity activity of extract on AGS and HeLa cell lines was evaluated by MTT assay 48 hours after treatment. The antioxidant activity of extract was 4.6 +/- 0.66 mu g/ml while it was 25.41 +/- 1.89 mu g/ml for butylated hydroxytoluene (BHT). The total phenol, flavonoid and flavonol contents were 269 mg GAE/g, 40.7 mg RUT/g and 88.12 mg RUT/g, respectively. The extract inhibited the proliferation of AGS, HeLa and HDFs cells with IC50 values of 382.3 mu g/m, 332.3 mu g/ml and 896.3, respectively. This study revealed that the extract of Pistacia atlantica can suppress the proliferation of gastric carcinoma and cervical cancer cells. The plant with high phytoconstituents could be a promising source of anticancer drugs.

Co-expressed differentially expressed genes and long non-coding RNAs involved in the celecoxib treatment of gastric cancer: An RNA sequencing analysis

Article

Full-text available

Sep 2016

The aim of the present study was to investigate the mechanisms of long non-coding RNAs (lncRNAs) in a gastric cancer cell line treated with celecoxib. The human gastric carcinoma cell line NCI-N87 was treated with 15 µM celecoxib for 72 h (celecoxib group) and an equal volume of dimethylsulfoxide (control group), respectively. Libraries were constructed by NEBNext Ultra RNA Library Prep kit for Illumina. Paired-end RNA sequencing reads were aligned to a human hg19 reference genome using TopHat2. Differentially expressed genes (DEGs) and lncRNAs were identified using Cuffdiff. Enrichment analysis was performed using GO-function package and KEGG profile in Bioconductor. A protein-protein interaction network was constructed using STRING database and module analysis was performed using ClusterONE plugin of Cytoscape. ATP5G1, ATP5G3, COX8A, CYC1, NDUFS3, UQCRC1, UQCRC2 and UQCRFS1 were enriched in the oxidative phosphorylation pathway. CXCL1, CXCL3, CXCL5 and CXCL8 were enriched in the chemokine signaling and cytokine-cytokine receptor interaction pathways. ITGA3, ITGA6, ITGB4, ITGB5, ITGB6 and ITGB8 were enriched in the integrin-mediated signaling pathway. DEGs co-expressed with lnc-SCD-1:13, lnc-LRR1-1:2, lnc-PTMS-1:3, lnc-S100P-3:1, lnc-AP000974.1-1:1 and lnc-RAB3IL1-2:1 were enriched in the pathways associated with cancer, such as the basal cell carcinoma pathway in cancer. In conclusion, these DEGs and differentially expressed lncRNAs may be important in the celecoxib treatment of gastric cancer.

Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer

Chapter

Aug 2016
ADV EXP MED BIOL

This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C. elegans. The contribution of major signaling pathways, e.g., Notch, Hedgehog, AKT/PI3K is discussed in the context of their potential contribution to foregut tumorigenesis. We critically examine the rationale behind specific GEMMs, chemical carcinogens, dietary promoters, Helicobacter infection, and direct mutagenesis of relevant oncogenes and tumor suppressor that have been developed to study gastric cancer pathogenesis. Despite species differences, more efficient and effective models to test specific genes and pathways disrupted in human gastric carcinogenesis have yet to emerge. As we better understand these species differences, “humanized” versions of mouse models will more closely approximate human gastric cancer pathogenesis. Towards that end, epigenetic marks on chromatin, the gut microbiota, and ways of manipulating the immune system will likely move center stage, permitting greater overlap between rodent and human cancer phenotypes thus providing a unified progression model.

The Effect of Some Immunomodulatory and Anti-Inflammatory Drugs on Li-Pilocarpine-Induced Epileptic Disorders in Wistar Rats

Article

Full-text available

Aug 2016
BRAIN RES

Evidence shows that inflammatory and immune processes within the brain might account for the pathophysiology of epilepsy. Therefore, developing new antiepileptic drugs that can modulate seizures through mechanisms other than traditional drugs is required for the treatment of refractory epilepsy. This study aims to determine the relationship between brain inflammation and epilepsy, to examine the contribution of some biochemical parameters involved in brain inflammation, and to address the effect of pharmacological interventions using some anti-inflammatory and immunomodulatory drugs in an experimental epilepsy model. Adult male rats were divided into seven groups of 20. G1 was the normal, non-treated control. G2 was the epileptic, non-treated group. G3–G7 were treated with celecoxib, methotrexate, azathioprine, dexamethasone, and valproate, respectively, for a period of three weeks. Induction of status epilepticus (SE) by Li-pilocarpine was performed on groups G2–G7. EEG tracing was conducted, and inflammatory mediators (brain and serum IL-1ß, IL 6, PGE2, HSP70, TGF-β2, and IFNγ) were measured. The induction of SE increased the amplitude and frequency of EEG tracing and inflammatory mediators more than in the normal control group. Treatments of epileptic rats reduced the frequency and amplitude of EEG tracing and significantly decreased the levels of inflammatory mediators in some treated rats compared to G2. These findings demonstrate that some anti-inflammatory and immunomodulatory drugs can lower the frequency and amplitude of seizures and reduce some inflammatory mediators in epilepsy treatments, strengthening the possibility that targeting these immunological and inflammatory pathways may represent another effective therapeutic approach to preventing epileptic seizures.

Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: A review and report of personal experience

Article

Full-text available

Mar 2006
WORLD J GASTROENTERO

Takashi Fujimura

Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were developed as one of the anti-inflammatory drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs (NSAIDs). However, coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis (FAP), which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration (FDA) immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum, and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors.

Expression of p-STAT3 and vascular endothelial growth factor in MNNG-induced precancerous lesions and gastric tumors in rats

Article

Full-text available

Mar 2016

Aim: To investigate the dynamic expression of p-signal transducer and activator of transcription 3 (STAT3) and vascular endothelial growth factor (VEGF) in the formation of gastric tumors induced by drinking water containing N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Wistar rats. Methods: One hundred and twenty Wistar rats were randomly divided into two groups (60 in each group): Control group and Model group. The rats in each group were then randomly divided into three groups (20 in each group): C/M15, C/M25 and C/M40 (15, 25 and 40 represent the number of feeding weeks from termination). Rats in the control group received normal drinking water and rats in the model group received drinking water containing 100 μg/mL MNNG. Stomach tissues were collected at the end of the 15(th), 25(th) and 40(th) week, respectively, for microscopic measurement using hematoxylin and eosin staining. The expression of p-STAT3 and VEGF in different pathological types of gastric tissue, including normal, inflammation, atrophy, hyperplasia and gastric stromal tumor, was observed by immunohistochemistry and Western blot, and the corelation between p-STAT3 and VEGF was analyzed. Results: (1) The expression of p-STAT3 in tissue with gastritis, atrophy, dysplasia and gastric stromal tumor were significantly increased in the model group compared with the control group (2.5 ± 1.0, 2.75 ± 0.36, 6.2 ± 0.45, 5.67 ± 0.55 vs 0.75 ± 0.36, P = 0.026, 0.035, 0.001, 0.002, respectively); the expression of p-STAT3 in tissue with dysplasia was higher than that in samples with gastritis or atrophy (6.2 ± 0.45 vs 2.5 ± 1.0, P = 0.006; 6.2 ± 0.45 vs 2.75 ± 0.36, P = 0.005, respectively); however, the expression of p-STAT3 in gastritis and atrophy was not significantly different (P > 0.05); (2) the expression of VEGF in tissue with gastritis, atrophy, dysplasia and gastric stromal tumor was significantly increased in the model group compared with normal gastric mucosa; and the expression of VEGF in tissue with dysplasia was higher than that in tissue with inflammation and atrophy (10.8 ± 1.96 vs 7.62 ± 0.25, P = 0.029; 10.8 ± 1.96 vs 6.26 ± 0.76, P = 0.033, respectively); similarly, the expression of VEGF in tissue with gastritis and atrophy was not significantly different (P > 0.05); and (3) the expression of VEGF was positively correlated with p-STAT3. Conclusion: p-STAT3 plays an important role in gastric cancer formation by regulating the expression of VEGF to promote the progression of gastric tumor from gastritis.

Molecular alterations in gastric cancer with special reference to the early-onset subtype

Article

Full-text available

Feb 2016
WORLD J GASTROENTERO

Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leaDing cause of cancer-related death worldwide. There are numerous possible factors that stimulate the procarcinogenic activity of important genes. These factors include genetic susceptibility expressed in a singlenucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g. , helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanDing features of EOGC.

The Role of Anti-LeY Antibody in the Downregulation of MAPKs/COX-2 Pathway in Gastric Cancer

Article

Full-text available

Feb 2014

Faisal Aziz

Monoclonal antibody-based treatments of cancer which serve as magic 'bullets' have been established as one of the most successful therapeutic strategies. A variety of antigens has been investigated as targets for the mAb therapy of gastric cancer, including the carbohydrate type 2 blood group antigen. Lewis Y (LeY) is overexpressed on tumor cells surface either as glycoproteins or glycolipids. LeY is difucosylated oligosaccharide with the chemical structure [Fuc1,2Gal14(Fuc1,3)GlcNAc1R], which is catalyzed by fucosyltransferases, such as FUT1 (1,2) and FUT4 (1,3). The role of LeY antigen in cancer treatment and prevention has been extensively studied. Moreover, the cyclooxy-genase-2 (COX-2) is an early event protein, highly expressed in H. pylori-related gastric cancer. COX-2 may play a piv-otal part in the maintenance of tumor viability, growth, and metastasis. The COX-2 is upregulated in a variety of cancers, including gastric cancer. However, its inhibition may prevent or reverse gastric carcinogenesis. H. pylori mediated alteration of COX-2 through MAPKs pathway is one of the mechanisms that is implicated in gastric cancer. We have found COX-2 and LeY to be correlative sources of specific gastric biomarkers in gastric cancer, which is upregulated in the gastric cancer through MAPKs pathway. In addition, the anti-LeY antibody significantly downregulated the COX-2 expression through MAPKs pathway, helpful to the treatment of gastric cancer. In this review, we summarize the therapeutic effect of anti-LeY antibody, including the crucial role of COX-2 and LeY antigen in gastric cancer and discuss the COX-2 inhibition by anti-LeY antibody through MAPKs pathway.

Effect of Ezhu on expression of cyclooxygenase, vascular endothelial growth factor and prostaglandin E2 in human gastric cancer cell line SGC7901

Article

Jun 2006

AIM: To investigate the effect of Ezhu on the expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2) in human gastric cancer cell line SGC7901. METHODS: The MTT method was used to observe the suppression of the human gastric cancer (SGC7901) cells treated with Ezhu. By drawing the suppression rate curves, we selected the appropriate Ezhu concentration at the 25% proliferation suppression rate as experimental concentration. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were adopted, respectively, to examine the expression of COX gene and protein. Furthermore, ELISA method was used to detect the variation of the VEGF and PEG2 expression in culture medium. RESULTS: Ezhu definitely inhibited the proliferation of human gastric cancer cells in a concentration dependent manner. Electrophoresis of the RT-PCR products demonstrated the expression of COX-1 and COX-2 gene in the human gastric cancer cells. Gray scale analysis showed that both Ezhu and celecoxib inhibited the expression of COX-1 and COX-2 gene, and the inhibitory action of Ezhu was greater than celecoxib. However, Western blot clearly showed that a specific protein strip was observed in COX-1 group at the 70 kDa, while in COX-2 group at the 80 kDa. Gray scale analysis confirmed than both Ezhu and celecoxib had apparent suppression on COX-2 protein, but had no effect on COX-1. Moreover, the suppression function of Ezhu surpassed celecoxib. Ezhu and celecoxib obviously degraded the content of VEGF in gastric cancer cells. In comparison with those in the control group, the results are statistically significant (91.0 ± 18.2, 127.8 ± 12.1 ng/L vs 162.0 ± 15.1 ng/L, P < 0.01). The level of PGE2 in the cells treated with celecoxib was lower than the control group with no statistical significance. Nevertheless, Ezhu decreased the level of PGE 2 significantly (67.5 ± 6.9 ng/L vs 78.7 ± 5.6 ng/L, P < 0.01). CONCLUSION: Ezhu can inhibit COX-2 and its downstream expression of PGE2, and down-regulates VEGF expression, so as to suppress the proliferation of gastric cancer cells.

Helicobacter pylori, cyclooxygenase-2 and evolution of gastric lesions: Results from an intervention trial in China

Article

Oct 2015
CARCINOGENESIS

To investigate the role of cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) in the process of Helicobacter pylori-induced gastric carcinogenesis, a prospective study based on an intervention trial was conducted in Linqu County, China. A total of 1401 subjects with histopathologic diagnosis were investigated at baseline, among those, 919 completed subsequent interventions (anti-H.pylori and/or celecoxib treatment). Expressions of COX-2 and Ki-67 were assessed by immunohistochemistry, and PGE2 levels were measured by enzyme immunoassay before and after interventions, respectively. We found a grade–response relationship between COX-2 expression level and risk of advanced gastric lesions at baseline. Stratified analysis indicated an additive interaction between COX-2 expression and H.pylori infection on the elevated risk of advanced gastric lesions. The odds ratios (ORs) for both factors combined were 9.31 [95% confidence interval (CI): 4.13–20.95] for chronic atrophic gastritis, 16.26 (95% CI: 7.29–36.24) for intestinal metaplasia and 21.13 (95% CI: 7.87–56.75) for dysplasia, respectively. After interventions, COX-2 expression and Ki-67 labeling index (LI) were decreased in anti-H.pylori group (OR: 1.65, 95% CI: 1.36–1.99 for COX-2; OR: 1.78, 95% CI: 1.49–2.12 for Ki-67) or anti-H.pylori followed by celecoxib group (OR: 1.41, 95% CI: 1.17–1.70 for COX-2; OR: 1.63, 95% CI: 1.37–1.94 for Ki-67). PGE2 levels were decreased in all treatment groups. Furthermore, the regression of gastric lesions was associated with the decrease of COX-2 expression or Ki-67 LI after interventions. Our findings indicate that H.pylori-induced COX-2/PGE2 pathways play an important role on the progression of precancerous gastric lesions in a Chinese population.

Helicobacter pylori infection, gastrin and cyclooxygenase-2 in gastric carcinogenesis

Article

Full-text available

Sep 2014
WORLD J GASTROENTERO

Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori (H. pylori) infection and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demonstrated that expression of cyclooxygenase-2 (COX-2) is elevated in gastric carcinomas and in their precursor lesions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.

The demethylase ALKBH5 mediates ZKSCAN3 expression through the m6A modification to activate VEGFA transcription and thus participates in MNNG-induced gastric cancer progression

Article

May 2024
J HAZARD MATER

Effects of Rutaecarpine on Chronic Atrophic Gastritis Through Nucleotide-binding Oligomerization Domain-like Receptors and Inflammasomes

Article

Mar 2024

Objective Chronic atrophic gastritis (CAG) is a complex and burdensome disease. However, side effects and compliance issues cannot be ignored due to the long treatment cycle. Numerous studies have confirmed the effectiveness of rutaecarpine (RUT) for treating digestive dysfunction. However, the potential mechanism of action of RUT in the context of CAG treatment remains unclear. This study aimed to explore the therapeutic effects and mechanisms of RUT in 1-methyl-3-nitro-1-nitrosoguanidine-induced CAG using network pharmacology, metabolomics, and traditional pharmacological approaches. Materials and Methods Pathological tests and ELISA assays were used to observe the therapeutic effects of RUT treatment on CAG. Differential metabolites were identified using ultra-high-performance liquid chromatography-tandem mass spectrometry, and metabolism-related target genes were enriched. The same target genes were identified between RUT and CAG diseases. The intersectional target genes were uploaded to Cytoscape for enrichment, and the nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway was selected to validate the mechanisms of the study. Finally, cell pyroptosis status was evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and the expressions of associated proteins of the NOD-like receptor signaling pathway were assessed by Western blotting and immunohistochemistry. Results RUT alleviated gastric mucosal damage and significantly downregulated indicators associated with inflammation and gastric atrophy. A total of 29 intersection target genes were identified, and core pathways were obtained. The NOD-like receptor signaling pathway and pyroptosis status were selected to validate the mechanisms of RUT treatment in CAG rats. The expression of NOD-related proteins and downstream factors was downregulated in the RUT group. Conclusions RUT exerts a pharmacological effect on relieving gastric damage in CAG rats by inhibiting NOD-like receptors and inflammasomes.

Chemical Design, Synthesis And Biological Evaluoation Of Mutual Prodrug Of Gabapentin With Different Types Of Phenolic And Alcoholic Antioxidants

Research

Jan 2021

This work concern about finding the best effective way to optimizing therapeutic characteristics of gabapentin, by retarding neuronal and gastrointestinal adverse effects through masking of carboxyl group chemically, and increase its analgesic This is achieved by design and synthesis different types of ester derivatives of gabapentin as mutual pro drugs with some of phenolic and alcoholic antioxidants. Pro moieties like; thymol and eugenol, umbilliferon and some other types of phenolic and alcoholic antioxidant ,with the aim of getting synergistic effect as these antioxidants considered as natural analgesic having analgesic and anti-inflammatory activity. The chemical structures of these compounds were confirmed and characterized using Fourier transform infrared spectroscopy (FTIR), 1H-NMR spectroscopy and some physicochemical parameters. The synthesized final compounds (3a-3g) were tested to evaluate their anti-inflammatory, antifungal and antibacterial activity against gram negative and gram positive bacteria. Anti-inflammatory activity in rats using egg-white induced edema method of inflammation. All of the synthesized compound showed anti-inflammatory activity compared to the control group (dimethyl sulfoxide) and gabapentin ; however eugenol conjugate (3f) and thymol conjugate (3a) demonstrate more significant anti-inflammatory activity than the other derivative. The antibacterial and antifungal activity for these compounds evaluated by well diffusion method and the results revealed that compound 3a have the best antibacterial and antifungal activity

Drug Repurposing in Gastric Cancer: Current Status and Future Perspectives

Chapter

Mar 2023

Gastric cancer remains an important contributor to the global cancer burden ranking the 5th most common and the 4th most deadly cancer, according to the latest cancer statistics. Despite the recent advances in the treatment of gastric cancer, with combinatorial and targeted therapies, the overall survival and cure rates are still poor, in particular for patients with advanced metastatic disease. Several reasons may explain the yet unsatisfactory clinical outcome of gastric cancer disease, from biological to experimental and conceptual, which should be tackled in an integrated manner to allow the development of better therapeutic options. Drug repurposing (DR, also known as drug repositioning) is gaining considerable attention as an additional strategy to the mainstream de novo drug discovery process. DR provides suitable drugs to expand the cancer chemotherapy options because it may explore the vast number of approved agents with known safety profiles. The opportunity to use repurposed drugs is grounded in the progress of the knowledge of cancer “physiology” and the consequent identification of more targetable pathways. It is also fostered by the possibility of the combined use of computational and bioinformatic tools, drug screening automation, sequencing technologies, and chemistry. Herein, after a brief introduction to gastric cancer facts and currently approved therapies, we review the current status of DR in gastric cancer mainly focusing on non-oncological drugs (i.e., drugs approved for diseases other than cancers) that have been under pre-clinical and clinical evaluation for cancer and compare the potential advantages and limitations of DR over the traditionally de novo development process. It will also be described the main strategies used to identify potentially “repurposable” drugs and discussed the challenges ahead for DR in gastric cancer.KeywordsGastric cancerDrug repurposingNon-cancer drugsPre-clinical studiesClinical trials

Chemical Design, Synthesis And Biological Evaluoation Of Mutual Prodrug Of Gabapentin With Different Types Of Phenolic And Alcoholic Antioxidants

Article

Full-text available

Jan 2021

Life, death, and inflammation: manipulation of phagocyte function by Helicobacter pylori

Chapter

Sep 2006

Lee-Ann H. Allen

This book provides up-to-date information on the crucial interaction of pathogenic bacteria and professional phagocytes, the host cells whose purpose is to ingest, kill, and digest bacteria in defense against infection. The introductory chapters focus on the receptors used by professional phagocytes to recognize and phagocytose bacteria, and the signal transduction events that are essential for phagocytosis of bacteria. Subsequent chapters discuss specific bacterial pathogens and the strategies they use in confronting professional phagocytes. Examples include Helicobacter pylori, Streptococcus pneumoniae, and Yersinae, each of which uses distinct mechanisms to avoid being phagocytosed and killed. Contrasting examples include Listeria monocytogenes and Mycobacterium tuberculosis, which survive and replicate intracellularly, and actually cooperate with phagocytes to promote their entry into these cells. Together, the contributions in this book provide an outstanding review of current knowledge regarding the mechanisms of phagocytosis and how specific pathogenic bacteria avoid or exploit these mechanisms.

Current Pharmaceutical Options for the Treatment of Rheumatoid Arthritis

Article

Full-text available

Dec 2019

Rheumatoid arthritis is an inflammatory and autoimmune disease that describes the joints persistent inflammation and tendon sheets synovial lining. The primary symptoms of rheumatoid arthritis are stiffness, pain, and swelling of peripheral joints. Persistent inflammation results in many systemic and extra-articular manifestations involving many organ systems. Rheumatoid arthritis treatment goals are symptomatic management of pain, stiffness and restricted mobility. NSAIDs are commonly prescribed for people with rheumatoid arthritis. Analgesic effects of NSAIDs are based mainly on the inhibition of COX-enzyme and consequently the production of prostaglandins.

Therapeutic Effects and Potential Mechanism of Dehydroevodiamine on N-Methyl-N′-Nitro-N-Nitrosoguanidine-Induced Chronic Atrophic Gastritis

Article

Jun 2021
PHYTOMEDICINE

Backgrounds: Dehydroevodiamine (DHE) is a quinazoline alkaloid isolated from a Chinese herbal medicine, named Euodiae Fructus (Wu-Zhu-Yu in Chinese). This study aimed to investigate the therapeutic effects and potential mechanism of DHE on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced chronic atrophic gastritis (CAG) based on integrated approaches. Methods: Therapeutic effects of DHE on serum biochemical indices and histopathology of gastric tissue in MNNG-induced CAG rats were analyzed. MNNG-induced GES-1 human gastric epithelial cell injury model was established. Cell viability and proliferation was quantified by a cell counting kit-8 assay. Cell morphology and mitochondrial membrane potential (MMP) were detected by a high content screening (HCS) assay. Cell migration and invasion were detected by a Transwell chamber. Moreover, UHPLC-Q-TOF/MS was performed to investigate the potential metabolites and signaling pathway affecting the protective effects of DHE on MNNG-induced cell migration and invasion of GES-1. Furthermore, in view of the key role of angiogenesis in the transformation of inflammation and cancer, this study explored relative mRNA and protein expression levels of HIF-mediated VEGF pathway in vivo and in vitro by RT-PCR and Western Blotting, respectively. Results: The results showed that the therapeutic effects of DHE on CAG rats were presented in down-regulation serum biochemical indices and alleviating histological damage of gastric tissue. Besides, DHE has an effect on increasing cell proliferation of GES-1 cells, ameliorating MNNG-induced gastric epithelial cell damage and mitochondrial dysfunction. In addition, DHE could inhibit MNNG induced migration and invasion of GES-1 cells. Cell metabolomics analyses showed that the protective effect of DHE on GES-1 cells is mainly associated with the regulation of inflammation metabolites and energy metabolism related pathways. It was found that DHE has a regulating effect on tumor angiogenesis and can inhibit the relative gene and protein expression of HIF-1α-mediated VEGF signaling pathway. Conclusions: The present work highlighted the role of DHE ameliorated gastric injury in MNNG-induced CAG rats in vivo and GES-1 cell migration in vitro by inhibiting HIF-1α/VEGF angiogenesis pathway. These results suggest that DHE may be the effective components of Euodiae Fructus, which provides a new agent for the treatment of CAG.

Astragaloside IV reverses MNNG-induced precancerous lesions of gastric carcinoma in rats: Regulation on glycolysis through miRNA-34a/LDHA pathway

Article

Mar 2018

This study was designed to investigate the precancerous lesions of gastric carcinoma (PLGC)‐reversing mechanisms of astragaloside IV (ASIV) in N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG)‐induced PLGC rats. All rats were sacrificed after 10‐week treatment. Gastric tissue was analyzed by using histopathology and electron microscope. To be fully evidenced, LDHA, p53, TIGAR, MCT1, MCT4, HIF‐1α, CD147, and miRNA‐34a were detected by Western blotting and Real‐time Quantitative polymerase chain reaction (RT‐qPCR). As histopathology and electron microscope showed, it can be clearly observed that the area of dysplasia was reduced in ASIV groups, indicating that MNNG‐induced PLGC was markedly reversed by ASIV. Moreover, compared with model group, a significant decrease in gene expressions of LDHA, MCT1, MCT4, HIF‐1α, CD147, and TIGAR was observed whereas miRNA‐34a level was increased in ASIV groups. A significant up‐regulation induced by MNNG in protein levels of LDHA, MCT1, MCT4, HIF‐1α, and CD147 was attenuated in rats treated with ASIV. In contrast, the decreased expression of TIGAR was restored by ASIV. Interestingly, up‐regulation of p53 expression induced by MNNG was further increased in ASIV groups. In brief, these results implied that abnormal glycolysis was relieved by ASIV via regulation of the expressions of LDHA, p53, TIGAR, MCT1, MCT4, HIF‐1α, CD147, and miRNA‐34a.

Nano-gold displayed anti-inflammatory property via NF-kB pathways by suppressing COX-2 activity

Article

Mar 2018

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, affecting almost 1% of world population. Although the exact cause of RA is not known but the complex interaction between inflammatory mediators like tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2) and nitric oxide (NO) is accountable for cartilage destruction in joints. Gold is used for arthritis treatment since long without knowing its mechanism of action. Hence, the present study was designed to assess antiarthritic activity of nanogold (AuNGs) in collagen-induced arthritic (CIA) rat model by virtue of decreasing inflammatory mediators and oxidative stress. After induction CIA rats were treated with AuNGs in phosphate buffer at a dose of 20 μg/kg body weight for 20 days and found a significant decrease in the level of inflammatory mediators like TNF-α, IL-1β, COX-2 and transcription factor NF-kB (Nuclear factor-kB), which was found to be elevated in CIA rats. Additionally imbalance in oxidant and antioxidant status were determined and perceived that AuNGs remarkably attenuates the imbalance in level of antioxidant and oxidant near to normal. In consistent to biochemical results, mRNA expression of NF-kB, TNF-α, COX-2, and iNOS were also up-regulated in CIA rats, which were considerably down regulated by AuNGs treatment. These findings were positively correlated with the histological results of joints, displayed reduced inflammation and bone erosion in treated group. This study demonstrates the ability of AuNGs to ameliorate production of inflammatory mediators and oxidative stress in CIA rats. Induction of arthritis in rats showed increased inflammation, which activate the transcription factor NF-kB through activation of of IkB kinases (IKK) and ubiquination/proteosome degradation of IKB and transportation of activated NF-kB from cytoplasm to nucleus. In nucleus activated NF-kB bind to the promoter region of target gene and up regulate the production of pro-inflammatory cytokines, COX-2 and other inflammatory mediators that leads to cartilage destruction. AuNGs inhibit the activation of NF-kB and other inflammatory mediators and attenuate inflammation and cartilage destruction. COX-2: cyclooxygenase-2; IKK: IkB kinases; IKB: I Kappa B; IL-1β: interleukin-6; IL-6: interleukin-6; iNOS: inducible nitric oxide synthase; NF-kB: nuclear transcription factor kappa B; ROS: reactive oxygen species; TNF-α: tumour necrosis factor-alpha.

Induction of Growth Inhibition and Apoptosis in Human Cancer Cells by a Brown Algae Extract

Article

May 2016

In this study, we investigated the effects of Undaria pinnatifida (UP), Petalonia binghamiae (PB) and Punctaria latifolia (PL) extracts on the inhibition of proliferation and apoptosis in human gastric and breast cancer cells. AGS, MDA-MB-231 and SK-BR-3 cells were treated with 0, 50, 100, and 200 ?g/ml concentrations of the extracts to determine their anti-proliferative effects, using the MTT assay. The UP, PB and PL extracts inhibited proliferation of AGS, MDA-MB-231 and SK-BR-3 cells in a dose-dependent manner, and the PL extract was found to be the most effective. DAPI staining was also performed to determine changes in the cell nucleus. Further, the AGS, MDA-MB-231 and SK-BR-3 cells were treated with 0, 50, 100, and 200 ?g/ml of only the PL extract. DAPI staining showed increased chromatin condensation, which is indicative of apoptosis, in the 200 ?g/ml group. The expression of the Bax, Bcl-2, and PARP proteins in AGS, MDA-MB-231 and SK-BR-3 cells treated with the PL extract was also determined by western blot analysis. The expression of Bax (a pro-apoptotic protein) and cleaved-PARP was increased, whereas the expression of Bcl-2 (an anti-apoptotic protein) was decreased compared with the control. These findings indicate that the PL extract may have potential as an alternative anticancer drug and nutraceutical.

The use of cyclooxygenase-2 inhibitors for improvement of efficacy of radiotherapy in cancers

Article

Mar 2016

Cyclooxygenase-2 (COX-2) is overexpressed in cancer cells and is associated with carcinogenesis and maintenance of progressive tumour growth as well as resistance of cancer cells to ionising radiation (IR). COX-2 inhibitors can attenuate tumour growth and expression of markers of cell proliferation as well as induce apoptosis in tumour cells. These agents can have a synergistic effect with IR in the killing of cancer cells. In this review, we discuss the rational basis and molecular mechanisms regarding the usefulness of COX-2 inhibitors in cancer therapy, and also their potential role in increasing the therapeutic index of chemoradiation by protecting normal cells and sensitising tumour cells to radiotherapy.

Molecular Targets for Antiinflammation and Dietary Component—Drug Synergy

Chapter

Aug 2005

Inflammation is a pathophysiological phenomenon that is involved in numerous diseases. Each human organ has the potential for diseases that possess an inflammatory condition essential to their etiology. A considerable proportion of chronic inflammatory diseases display an overlap with the onset and development of cancer, such as ulcerative colitis and Crohn’s disease (colorectal cancer), reflux esophagitis, Barrett’s esophagus (esophageal carcinoma), and hepatitis (hepatocellular carcinoma). Further, we know that inflammation plays a pivotal role in insulin resistance, obesity, and diabetes, as well as in brain and myocardial infarctions that originate from vascular atherosclerosis. Thus, regulation of inflammatory conditions with food and drugs that are designed from a mechanistic viewpoint should provide great benefit for health promotion and disease prevention.

Cyclooxygenase II - A role in gastric cancer treatment

Article

Jan 2007

Recent studies have demonstrated that increased amount of prostaglandin E2 (PGE2) produced by overexpression of cyclooxygenase-2 (COX-2)/microsomal PGE synthase-1 (mPGES-1) is involved in tumor proliferation. Furthermore, relationships with epidermal growth factor (EGF)/mitogen activated protein (MAP) kinase signal pathway related to cell proliferation and Akt/protein kinase B (PKB) related to resistance of apoptosis are being clarified. Association of COX-2 with gastric cancer has not been established as clearly as in colon cancer. However, increased expression of COX-2 in gastric cancer was confirmed, and in cell culture or animal models, influence of COX-2 on tumor proliferation was indicated. Thus, the usefulness of COX-2 inhibitor in treatment has been demonstrated. However, in precancerous lesions of gastric cancer, COX-2 expression is controversial and the usefulness of COX-2 inhibitor has not been demonstrated. Further studies about COX-2 and gastric cancer including clinical trials are needed, and also more studies should be performed about other PGE2 related enzymes as well as COX-2.

Chemoprevention of Pancreatic Carcinogenesis

Article

Jan 2009

The present study was designed to establish if Etodolac, a selective cyclooxygenase-2 inhibitor, prevents chemically induced intraductal papillary carcinoma (IPC) in the main pancreatic duct of hamsters. Hamsters were subjected to cholecystoduodenostomy with dissection of the distal end of the common duct. Four weeks after surgery, the surviving hamsters were given subcutaneous injections of N-nitrosobis(2-oxopropyl)amine (BOP) 10 mg/kg body weight, every 2 weeks, four times. The animals were divided into three groups based on the simultaneous oral intake of a CE-2 pelleted diet, which contained 0% (group CE, n = 30), 0.01% (group ET, n = 21), or 0.04% Etodolac (group ET4, n = 25), respectively. Hamsters were killed for pathological examination 36 weeks after the operation. The incidence of induced pancreatic carcinoma was 93%, 81%, and 72% in groups CE, ET, and ET4, respectively. The pancreatic carcinomas were classified into four histological types: tubular, papillary, and cystic adenocarcinoma, and IPC. The incidence of IPC and the number of IPCs per animal were significantly lower in groups ET4 (36% and 0.48) and ET (48% and 0.62) than in group CE (67% and 1.30). The proliferating cell nuclear antigen labeling indices in the noncancerous epithelial cells of the main pancreatic duct were 2.8% and 6.8% in groups ET4 and ET, respectively; being significantly lower than that in group CE (10.8%). In conclusion, Etodolac inhibited BOP-induced IPC in hamsters. The suppression of epithelial cell proliferation of the main pancreatic duct was considered a possible mechanism of cancer prevention in this hamster model.

Chemoprevention of Biliary Carcinogenesis

Article

Jan 2009

This study was conducted to find out if etodolac, a cyclooxgenase-2 (COX-2)-specific inhibitor, could prevent chemically induced biliary carcinogenesis in bilioenterostomized hamsters. Syrian golden hamsters were subjected to choledochojejunostomy and then given subcutaneous injections of N-nitrosobis (2-oxopropyl)amine (BOP) 10 mg/kg body weight every 2 weeks. BOP was started 4 weeks after surgery, and continued for 18 weeks. The animals were simultaneously given etodolac 10 mg/kg body weight in 0.5% methylcellulose solution orally three times per week (etodolac group). The control hamsters were administered methylcellulose solution alone. The hamsters were killed 22 weeks after surgery, and the biliary carcinomas were examined histologically. The presence and degree of cholangitis and the cell kinetic status of the biliary epithelium were also evaluated with special reference to biliary carcinogenesis. Intrahepatic bile duct carcinomas developed in 15 (88%) of 17 hamsters in the control group, but in only 6 (33%) of 18 hamsters in the etodolac group (P < 0.01). The incidence and number of developing biliary carcinomas correlated well with the degree of cholangitis, and severe cholangitis was evident in the controls. The cell kinetic study demonstrated that the proliferating cell nuclear antigen-labeling index of the biliary epithelium was 9.67% in the control group and 5.14% in the etodolac group (P < 0.05). The mean levels of prostaglandin E2 (PGE2) products in the liver tissue were 14.14 ± 3.31 pg/total protein (TP) mg in the control group, and 7.46 ± 2.34 pg/TP mg in the etodolac group (P < 0.05). These findings indicated that etodolac inhibited the occurrence of severe cholangitis and the acceleration of biliary epithelial cell kinetics after bilioenterostomy, thereby preventing BOP-induced biliary carcinogenesis in hamsters. In conclusion, the COX-2-specific inhibitor, etodolac, could be used to prevent not only reflux cholangitis, but also biliary carcinoma after bilioenterostomy.

The effect of helicobacter pylori colonization on enterochromaffin-like (ECL) cell and gastrin (G) positive cells in rat stomach

Article

Jul 2014

Background: Enterochromaffin-like (ECL) cells have an important role in the gastric tissues. Helicobacter pylori (H. pylori) colonization has effect on function and the number of these cells. The aim of this study was to investigate the effect of 20-weeks Helicobacter pylori colonization on ECL and gastrin (G) positive cells in rat gastric tissues. Methods: 10 rats were divided equally in two experimental and control groups. Then, Helicobacter pylori or phosphate buffered saline (PBS) were gavaged to experimental and control groups three times a week for 20 weeks, respectively. Bacterial colonization and histopathological features of gastric tissues were examined with hematoxylin-eosin and Giemsa stains. ECL and G cells were investigated in gastric tissues with silver staining and immunohistochemistry (IHC) methods. Findings: After 20 weeks of gavage, Helicobacter pylori colonization was seen in the gastric tissues. Histopathological changes including epithelial disorganization, epithelial vacuolization, lamina propria and epithelium irregularities in the experimental group were seen. Silver staining showed that the mean number of ECL cells was 11.76 ± 1.79 and 8.35 ± 1.34 cells/volume unit in experimental and control groups, respectively (P < 0.001). Immunohistochemistry staining showed that mean number of G cells was 6.74 ± 1.21 and 3.65 ± 0.08 cells/volume unit in experimental and control groups, respectively (P < 0.001). Conclusion: This study showed that colonization of Helicobacter pylori induces epithelial disorganization and vacuolization, lamina propria and epithelium irregularities in gastric tissues and also increases the number of ECL and G cells in these tissues. © 2014, Isfahan University of Medical Sciences(IUMS). All rights reserved.

Effects of microRNA-155 on mice with lipopolysaccharide-induced acute lung injury

Article

Jul 2015

Objective To study the effects of mic.roRNA (miR) -155 on mice, with acute lung injury induced by lipopolysaccharide (LPS). Methods According to the random number table, 30 C57 mice were divided into group LPS, group miR-155 inhibitor, group miR control, group miR-155 mimics, normal control group, with 6 mice in each group. Mice in group LPS and the other three treatment groups were given 5 μl LPS (20 μg/μl, in the dose of 4 mg/kg) to reproduce acute lung injury model. Half an hour after injury, group LPS, group miR-155 inhibitor, group miR control, group miR-155 mimics were injected with saline, miR-155 inhibitor, miR control and miR-155 mimics through trachea. Mice in normal control group were received no treatment. All mice were anesthetized after 24 h, while lung tissue samples were harvested for histomorphological observation, detection of mRNA expressions of tumor necrosis factor-α (TNF-a) , interleukin-1 β (IL-lβ) with SYBR Green real-time polymerase chain reaction (PCR) , detection of miR-155 in group miR-155 inhibitor, group miR control, group miR-155 mimics by Taqman PCR. The protein expression of cyclooxygenase-2 ( COX-2) was determined by western blot. Data were statistically analyzed. Results The relative mRNA expression values of TNF-a were 24. 49 ± 3. 64, 38. 92 ± 3. 40, 36. 00 ±3. 86, 12. 56 ±2. 06, 1.04 ±0.41 in group LPS, group miR-155 inhibitor, group miR control, group miR-155 mimics, normal control group. The relative mRNA expression values of 1L.-1β were 55. 96 ± 4.87, 62. 90 ±6. 41, 59. 99 ±6. 48, 25.33 ±3.50, 1. 11 ±0.44 in group LPS, group miR-155 inhibitor, group miR control, group miR-155 mimics, normal control group. The differences of TNF-α and IL-β (3 in group miR-155 mimics were statistically significant by compared with group LPS, group miR-155 inhibitor, group miR control ( P < 0. 05). The differences were not statistically significant among group LPS, group miR-155 inhibitor, group miR control. Western blot analysis showed the relative expression values of COX-2 were 0. 94 ± 0. 06, 0. 96 ± 0. 09, 0.91 ±0.03, 0.79 ±0.04, 0.63 ±0.07 in group LPS, group miR-155 inhibitor, group miR control, miR-155 mimics and normal control group. The value in normal control group was significantly lower than other groups (P <0.05). Conclusion Lsing the miR-155 can effectively alleviate the lung inflammation in mice with acute lung injurv induced In LPS.

Chemoprevention trials of GI cancers in Asia

Article

Sep 2015

Cancers are among the leading causes of morbidity and mortality worldwide, with gastrointestinal (GI) luminal cancers accounting for a large proportion of cancer incidence. Chemoprevention of GI luminal cancers is important to reduce this cancer burden. Screening for and eradication of Helicobacter pylori (H. pylori) in areas with high gastric cancer incidence is a safe and effective strategy to decrease the incidence of gastric cancer. Eradication of H. pylori also seems to be effective in preventing metachronous cancer development after endoscopic resection of early gastric cancer. For the average risk individual, COX inhibitors may have a role in reducing the incidence of adenoma formation as well as colorectal cancer, bearing in mind its inherent risks. There is currently insufficient evidence to recommend a chemoprevention agent against esophageal and small intestine cancer.

Short-term Celecoxib intervention is a safe and effective chemopreventive for gastric carcinogenesis based on a Mongolian gerbil model

Article

Oct 2009
WORLD J GASTROENTERO

Chao-Hung Kuo

AIM: To evaluate the optimal intervention point of a selective cyclooxygenase-2 (COX-2) inhibitor, Celecoxib, for inhibiting Helicobacter pylori (H pylori)-associated gastric carcinogenesis in Mongolian gerbils (MGs). METHODS: One hundred and twelve MGs were divided into six groups (A-F). One hundred gerbils were inoculated with H pylori (groups A-E). Twelve gerbils were inoculated with vehicle broth only (group F). After 4 wk, they were given N’-methyl-N’-nitro-N-nitroso-guanidine (MNNG) (50 μg/mL) in the drinking water for 20 wk. In groups B-E, the animals were given the stock Celecoxib (10 mg/kg per day) diet from the 21st, 31st, 21st and 41st week respectively. The periods of administering Celecoxib were 30, 20, 20, and 15 wk respectively. On the 51st week, the animals were sacrificed for histological examination. Local PCNA expression was examined by the immunohistochemistry method. The expression of COX-2 protein was assessed by Western Blot. Analysis used the χ2 test. The difference was regarded as significant when P value was less than 0.05. RESULTS: Seventeen percent (17/100) of H pylori-infected MGs developed gastric cancer. All of these lesions were well-differentiated adenocarcinoma. The incidence rates of adenocarcinoma in groups A-F were 40%, 0%, 0%, 20%, 25%, and 0% respectively. The inflammatory scores were higher in group B than in other groups. There was no inflammatory response noted in group F. Celecoxib treatment resulted in a significant reduction in the proliferation of H pylori-infected mucosal cells (groups B, C and D) (P < 0.01).The expression of COX-2 protein was significantly attenuated in the groups which were Celecoxib-treated for more than 20 wk (groups B, C, D). The groups treated with Celecoxib had a significantly lower rate of advanced gastric cancer (34% vs 75%, P < 0.001) There were no sudden deaths in any of the groups. CONCLUSION: Short-term treatment with Celecoxib has an anti-carcinogenic effect, and resulted in less severe inflammation and inhibited the invasive degree of gastric cancer.

Anti-Helicobacter pylori therapy followed by celecoxib on progression of gastric precancerous lesions

Article

Jun 2009
WORLD J GASTROENTERO

Li-Jing Zhang

Chemoprevention of colon carcinogenesis by Sulindac, a nonsteroidal anti-inflammatory agent

Article

Full-text available

Apr 1995

Epidemiological and laboratory animal model studies have suggested that nonsteroidal anti-inflammatory drugs reduce the risk of development of colon cancer. The present study was designed to investigate the chemopreventive action of 160 and 320 ppm (equivalent to 40 and 80% maximum tolerated doses) sulindac, a nonsteroidal anti-inflammatory drug, fed during initiation and postinitiation stages and 320 ppm sulindac fed during promotion/progression stages of azoxymethane-induced colon carcinogenesis in male F344 rats. Also investigated was the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phosphatidylinositol-specific phospholipase C, lipoxygenase, and cyclooxygenase activities. At 5 weeks of age, groups of male F344 rats were fed control diet or diets containing 160 and 320 ppm of sulindac. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. Animals intended for tumor promotion/progression study were administered 320 ppm of sulindac in diet starting at 14 weeks after a second azoxymethane treatment. All animals continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phosphatidylinositol-specific phospholipase C, prostaglandin E2, cyclooxygenase, and lipoxygenase activities. The levels of sulindac and its metabolites in stomach, cecal, and fecal contents and in serum were analyzed. The results indicate that dietary sulindac at 160 and 320 ppm levels inhibited the incidence of invasive and noninvasive adenocarcinomas of the colon (P < 0.01-0.001) as well as their multiplicity (P < 0.01-0.0001) in a dose-dependent manner. Also, feeding sulindac during promotion/progression stages significantly suppressed the incidence (P < 0.0001) and multiplicity (P < 0.0001) of colonic adenocarcinomas. Dietary sulindac also suppressed the colon tumor volume by > 52-62% compared to the control diet. Dietary sulindac significantly decreased the activities of phosphatidylinositol-specific phospholipase C (32-51%) and levels of prostaglandin E2 (> 40%) in the colonic mucosa and tumors, but it had no significant (P > 0.05) effect on phospholipase A2 activity. The formation of cyclooxygenase metabolites, particularly prostaglandin E2, prostaglandin F2 alpha, prostaglandin D2, 6-ketoprostaglandin F1 alpha, and thromboxane B2, and lipoxygenase metabolites such as 8(S)- and 12(S)-hydroxyeicosatetraenoic acids were significantly reduced in colonic mucosa and tumors of animals fed 320 ppm sulindac.(ABSTRACT TRUNCATED AT 400 WORDS)

Kawamori, K, Rao, CV, Seibert, K & Reddy, BSC. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res 58: 409-412

Article

Full-text available

Mar 1998

Epidemiological and laboratory studies suggest that nonsteroidal antiinflammatory drugs reduce the risk of colon cancer and that the inhibition of colon carcinogenesis is mediated through modulation of prostaglandin production by cyclooxygenase (COX) isozymes (COX-1 and -2). Overexpression of COX-2 has been observed in colon tumors; therefore, specific inhibitors of COX-2 activity could potentially serve as chemopreventive agents. Our recent study indicated that celecoxib (SC-58635), a specific COX-2 inhibitor, suppressed colonic aberrant crypt foci formation induced by azoxymethane in rats and led us to investigate more specifically the chemopreventive potential of this compound using colon tumors as end points. Five-week-old male F344 rats were fed the control diet (modified AIN-76A) or an experimental diet containing 1500 ppm celecoxib. Two weeks later, all animals except those in the saline-treated groups received s.c. injections of azoxymethane (15 mg/kg of body weight) once weekly for 2 weeks. All groups were kept on their regimen until the experiment was terminated, 50 weeks after carcinogen treatment. Colon tumors were evaluated histopathologically. Remarkably, dietary administration of celecoxib inhibited both incidence and multiplicity of colon tumors by about 93 and 97%, respectively. It also suppressed the overall colon tumor burden by more than 87%. The degree of tumor inhibition was more pronounced with celecoxib than it was with previously evaluated nonsteroidal anti-inflammatory drugs. The results of this study provide evidence, for the first time, that a specific COX-2 inhibitor, celecoxib, possesses strong chemopreventive activity against colon carcinogenesis.

Chromosomal mapping of genes controlling development, histological grade, depth of invasion, and size of rat stomach carcinomas

Article

Full-text available

Mar 2000

Rat stomach cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are widely used as a model of differentiated-type human stomach cancers. ACI/N (ACT) rats are susceptible and BUF/Nac (BUF) rats are resistant to MNNG-induced stomach carcinogenesis, and the presence of an autosomal gene with a dominant BUF allele has been suggested. In this study, we performed a carcinogenicity test by giving MNNG in drinking water to 117 male ACI x (ACIxBUF)F1 backcross rats. Each of 100 effective rats was diagnosed for its "carcinoma development" and when it was bearing stomach carcinoma(s), for histological grade, depth of invasion, and size and number of tumors. Carcinoma development was diagnosed based both on the age of the rat and on the presence of stomach carcinoma(s). Linkage analysis was performed with the genotypes of 161 loci, covering 1637 cM of the rat genome. Contrary to our original expectations, the most influential gene was the one on chromosome (chr.) 15, Gastric cancer susceptibility gene 1 (Gcs1), which confers susceptibility to stomach carcinogenesis (LOD, 3.8) with a dominant BUF allele by promoting conversion from adenomas to carcinomas. Two resistance genes on chr. 4 and chr. 3, Gastric cancer resistance gene 1 (Gcr1) and Gcr2, were shown to confer dominant resistance (LOD, 2.7 and 2.6, respectively). Gcs1, Gcr1, and Gcr2 exerted additive effects on the development of stomach carcinomas. A gene on chr. 16, Gcr3, was indicated to reduce the depth of invasion (LOD, 2.2) and sizes of tumors (LOD, 1.9). No linkage was obtained using the number of tumors. These findings show that the coordinate effect of a susceptibility gene, Gcs1, and two resistance genes, Gcr1 and Gcr2, is responsible for the development of MNNG-induced stomach carcinomas and that Gcr3 is responsible for the growth of a stomach carcinoma, reflected in the depth of invasion and in the tumor size.

The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor, in Familial Adenomatous Polyposis

Article

Full-text available

Jul 2000

Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.

RESPONSE: Re: Chemoprevention of Gastric Dysplasia: Randomized Trial of Antioxidant Supplements and Anti-Helicobacter pylori Therapy

Article

Full-text available

Apr 2001

Previous research has identified a high risk of gastric carcinoma as well as a high prevalence of cancer precursor lesions in rural populations living in the province of Nariño, Colombia, in the Andes Mountains. A randomized, controlled chemoprevention trial was conducted in subjects with confirmed histologic diagnoses of multifocal nonmetaplastic atrophy and/or intestinal metaplasia, two precancerous lesions. Individuals were assigned to receive anti-Helicobacter pylori triple therapy and/or dietary supplementation with ascorbic acid, beta-carotene, or their corresponding placebos. Gastric biopsy specimens taken at baseline were compared with those taken at 72 months. Relative risks of progression, no change, and regression from multifocal nonmetaplastic atrophy and intestinal metaplasia were analyzed with multivariate polytomous logistic regression models to estimate treatment effects. All statistical tests were two-sided. All three basic interventions resulted in statistically significant increases in the rates of regression: Relative risks were 4.8 (95% confidence interval [CI] = 1.6-14.2) for anti-H. pylori treatment, 5. 1 (95% CI = 1.7-15.0) for beta-carotene treatment, and 5.0 (95% CI = 1.7-14.4) for ascorbic acid treatment in subjects with atrophy. Corresponding relative risks of regression in subjects with intestinal metaplasia were 3.1 (95% CI = 1.0-9.3), 3.4 (95% CI = 1.1-9.8), and 3.3 (95% CI = 1.1-9.5). Combinations of treatments did not statistically significantly increase the regression rates. Curing the H. pylori infection (which occurred in 74% of the treated subjects) produced a marked and statistically significant increase in the rate of regression of the precursor lesions (relative risks = 8.7 [95% CI = 2.7-28.2] for subjects with atrophy and 5.4 [95% CI = 1.7-17.6] for subjects with intestinal metaplasia). In the very high-risk population studied, effective anti-H. pylori treatment and dietary supplementation with antioxidant micronutrients may interfere with the precancerous process, mostly by increasing the rate of regression of cancer precursor lesions, and may be an effective strategy to prevent gastric carcinoma.

Association between cyclo-oxygenase 2 overexpression and missense mutations in gastric cancer

Article

Full-text available

Mar 2001

Wild-type p53 competitively binds to the promoter region of COX-2 in vitro and inhibits its transcription. We examined the association between p53 mutation and COX-2 expression in gastric cancer. COX-2 over-expression was seen in 19 (48.7%) cases. These tumours had more lymph-node metastasis (P = 0.048) and tended to have a poorer survival (P = 0.07). Missense mutations of p53 were detected in 20 (51.3%) patients and had a significantly stronger COX-2 expression than tumours without p53 mutation (P = 0.016). Our results suggest a link between p53 mutation and COX-2 overexpression in gastric cancer.

Helicobacter pylori Infection and the Development of Gastric Cancer

Article

Full-text available

Oct 2001

Although many studies have found an association between Helicobacter pylori infection and the development of gastric cancer, many aspects of this relation remain uncertain. We prospectively studied 1526 Japanese patients who had duodenal ulcers, gastric ulcers, gastric hyperplasia, or nonulcer dyspepsia at the time of enrollment; 1246 had H. pylori infection and 280 did not. The mean follow-up was 7.8 years (range, 1.0 to 10.6). Patients underwent endoscopy with biopsy at enrollment and then between one and three years after enrollment. H. pylori infection was assessed by histologic examination, serologic testing, and rapid urease tests and was defined by a positive result on any of these tests. Gastric cancers developed in 36 (2.9 percent) of the infected and none of the uninfected patients. There were 23 intestinal-type and 13 diffuse-type cancers. Among the patients with H. pylori infection, those with severe gastric atrophy, corpus-predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer. We detected gastric cancers in 21 (4.7 percent) of the 445 patients with nonulcer dyspepsia, 10 (3.4 percent) of the 297 with gastric ulcers, 5 (2.2 percent) of the 229 with gastric hyperplastic polyps, and none of the 275 with duodenal ulcers. Gastric cancer develops in persons infected with H. pylori but not in uninfected persons. Those with histologic findings of severe gastric atrophy, corpus-predominant gastritis, or intestinal metaplasia are at increased risk. Persons with H. pylori infection and nonulcer dyspepsia, gastric ulcers, or gastric hyperplastic polyps are also at risk, but those with duodenal ulcers are not.

Piroxicam is an ineffective inhibitor of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus

Article

Full-text available

Sep 2002

Epidemiological studies indicate an association between the frequent use of nonsteroidal anti-inflammatory drugs and decreased risk for esophageal cancer. These studies suggest that limiting excess prostaglandin production, via inhibition of cyclooxygenase (COX)-mediated arachidonic acid metabolism, may be an important strategy for the prevention of this type of malignancy. N-Nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus is a model of human esophageal squamous cell carcinoma used for investigations of chemical carcinogenesis and for the evaluation of putative chemopreventive agents. In this study, we characterized COX-mediated arachidonic acid metabolism in NMBA-induced rat esophageal tumorigenesis by measuring COX-1 and COX-2 expression and prostaglandin E(2) production. In addition, we evaluated the ability of piroxicam, a potent COX inhibitor, to prevent postinitiation events of NMBA-induced tumorigenesis in the rat esophagus. After a 2-week acclimatization period, groups of 30 male F344 rats received s.c. injections of NMBA (0.5 mg/kg b.w.) three times/week for 5 weeks. Seventy-two h after the final NMBA treatment and for the remainder of the study, piroxicam was administered in the diet at 200 and 400 ppm. Twenty-five weeks after the initiation of NMBA treatment, we observed an elevation in COX mRNA and protein expression and prostaglandin E(2) production in NMBA-treated esophageal tissues compared with normal epithelium. However, these changes were associated with data indicating that a COX inhibitor is not preventive in NMBA-induced rat esophageal tumorigenesis. Administration of piroxicam in the diet produced no significant reductions in esophageal tumor incidence, multiplicity, or size. The reasons for the lack of effect are largely unknown but may be related to the inability of piroxicam to modulate other biochemical pathways involved in NMBA-induced tumorigenesis.

A Randomized Trial of Aspirin to Prevent Colorectal Adenomas

Article

Full-text available

Apr 2003
NEW ENGL J MED

Laboratory and epidemiologic data suggest that aspirin has an antineoplastic effect in the large bowel. We performed a randomized, double-blind trial of aspirin as a chemopreventive agent against colorectal adenomas. We randomly assigned 1121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81 mg of aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to the protocol, follow-up colonoscopy was to be performed approximately three years after the qualifying endoscopy. We compared the groups with respect to the risk of one or more neoplasms (adenomas or colorectal cancer) at least one year after randomization using generalized linear models to compute risk ratios and 95 percent confidence intervals. Reported adherence to study medications and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up colonoscopy was performed at least one year after randomization in 1084 patients (97 percent). The incidence of one or more adenomas was 47 percent in the placebo group, 38 percent in the group given 81 mg of aspirin per day, and 45 percent in the group given 325 mg of aspirin per day (global P=0.04). Unadjusted relative risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg group (95 percent confidence interval, 0.69 to 0.96) and 0.96 in the 325-mg group (95 percent confidence interval, 0.81 to 1.13). For advanced neoplasms (adenomas measuring at least 1 cm in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer), the respective relative risks were 0.59 (95 percent confidence interval, 0.38 to 0.92) and 0.83 (95 percent confidence interval, 0.55 to 1.23). Low-dose aspirin has a moderate chemopreventive effect on adenomas in the large bowel.

Effects in Rats of Sodium Chloride on Experimental Gastric Cancers Induced by N-Methyl-N′-nitro-N-nitrosoguanidine or 4-Nitroquinoline-1-oxide2

Article

Jul 1975

The effects were studied of NaCl on the production of gastric carcinomas by N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and by 4-nitroquinoline-1-oxide (NQO) in male Wistar rats. Nine groups of rats were treated as follows: Group 1 was given 50 mg MNNG/liter and 6 g NaCl solution/liter to drink and was fed a stock diet supplemented with 10% NaCl. Group 2 received 1 ml saturated NaCl once a week and 50 mg MNNG/liter to drink. Group 3 was treated with MNNG alone. Group 4 was given a solution of 1 mg NQO once a week and fed a stock diet supplemented with 10% NaCl. Group 5 received a solution of 1 mg NQO saturated with NaCl. Group 6 was given NQO alone. Groups 7 and 8 were given NaCl alone. Group 9 was untreated. Adenocarcinomas developed in the glandular stomach in group 2 at a significantly higher incidence than in group 3. Poorly differentiated adenocarcinomas of the glandular stomach were detected in only groups 1 and 2. One poorly differentiated adenocarcinoma metastasized to the lymph nodes. A high incidence of squamous cell carcinomas of the forestomach was found in groups 4 and 5. No malignant tumors were seen in groups 6-9. NaCl given alone had no apparent carcinogenicity in rats but, when administered with MNNG or NQO, it enhanced the carcinogenic effects of MNNG and NQO in the stomach

Inhibition by rat C‐erbB‐2/neu antisense oligonucleotide of gastric carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine in wistar rats

Article

Nov 1999
INT J CANCER

The effect of prolonged administration of a rat C-erbB-2/neu (C-erbB-2) antisense oligonucleotide on gastric carcinogenesis induced by N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and on the labeling and apoptotic indices of gastric cancer was examined in Wistar rats After oral treatment with MNNG for 25 weeks, the rats received intraperitoneal injections of a C-erbB-2 antisense-liposome complex or a sense-liposome complex at a dose of 50 μg oligonucleotide/kg body weight every other day until the end of the experiment in week 52. In week 52, the incidence of gastric cancers was significantly lover in rats treated with the C-erbB-2 antisense oligonucleotide than in rats treated with the sense oligonucleotide. Administration of the C-erbB-2 antisense oligonucleotide also significantly decreased the bromodeoxyuridine-labeling index and significantly increased the apoptotic index of gastric cancers. The mean cellular fluorescence of gastric antral cells in MNNG-treated rats was positively correlated with the dose of FITC-labeled C-erbB-2 antisense oligonucleotide. Our findings indicate that the antisense oligonucleotide inhibits gastric carcinogenesis through decreased cell proliferation and increased apoptosis induction and suggest that antisense strategies may provide new treatment for gastric cancer. Int. J. Cancer, 83:670–673, 1999.

Aspirin Use and Colorectal Cancer: Post-Trial Follow-up Data from the Physicians' Health Study

Article

May 1998

Til Sturmer

Background: In contrast to most observational studies, the randomized Physicians' Health Study found no association between aspirin use and colorectal cancer after 5 years. Objective: To determine the effect of randomly assigned aspirin treatment and self-selected aspirin use on the incidence of colorectal cancer after 12 years and to identify factors influencing the self-selection of regular aspirin use. Design: Randomized clinical trial and prospective cohort study. Setting: Male physicians throughout the United States. Patients: 22 071 healthy male physicians who were 40 to 84 years of age in 1982. Intervention: 325 mg of aspirin every other day. In 1988, the aspirin arm of the randomized trial was stopped early. Participants then chose to receive either aspirin or placebo for the rest of the study. Measurements: Annual questionnaires asking about aspirin use and other variables, including occurrence of cancer. Results: Colorectal cancer was diagnosed in 341 patients during the study period. Over 12 years of follow-up, random assignment to aspirin was associated with a relative risk for colorectal cancer of 1.03 (95% Cl, 0.83 to 1.28). Various gastrointestinal symptoms and diagnoses were strong predictors of less frequent aspirin use in 1988. The relative risk for colorectal cancer in persons who used aspirin frequently after 1988 was 1.07 (Cl, 0.75 to 1.53). Conclusions: In the Physicians' Health Study, both randomized and observational analyses indicate that there is no association between the use of aspirin and the incidence of colorectal cancer. The low dose of aspirin used and the short treatment period may account for the null findings. However, other characteristics associated with the use of aspirin in observational studies remain a plausible alternative explanation.

Chemoprevention of Gastric Dysplasia: Randomized Trial of Antioxidant Supplements and Anti-Helicobacter pylori Therapy

Article

Dec 2000
J NATL CANCER I

Pelayo Correa

Background: Previous research has identified a high risk of gastric carcinoma as well as a high prevalence of cancer precursor lesions in rural populations living in the province of Nariño, Colombia, in the Andes Mountains. Methods: A randomized, controlled chemoprevention trial was conducted in subjects with confirmed histologic diagnoses of multifocal nonmetaplastic atrophy and/or intestinal metaplasia, two precancerous lesions. Individuals were assigned to receive anti-Helicobacter pylori triple therapy and/or dietary supplementation with ascorbic acid, β-carotene, or their corresponding placebos. Gastric biopsy specimens taken at baseline were compared with those taken at 72 months. Relative risks of progression, no change, and regression from multifocal nonmetaplastic atrophy and intestinal metaplasia were analyzed with multivariate polytomous logistic regression models to estimate treatment effects. All statistical tests were two-sided. Results: All three basic interventions resulted in statistically significant increases in the rates of regression: Relative risks were 4.8 (95% confidence interval [CI] = 1.6–14.2) for anti-H. pylori treatment, 5.1 (95% CI = 1.7–15.0) for β-carotene treatment, and 5.0 (95% CI = 1.7–14.4) for ascorbic acid treatment in subjects with atrophy. Corresponding relative risks of regression in subjects with intestinal metaplasia were 3.1 (95% CI = 1.0–9.3), 3.4 (95% CI = 1.1–9.8), and 3.3 (95% CI = 1.1–9.5). Combinations of treatments did not statistically significantly increase the regression rates. Curing the H. pylori infection (which occurred in 74% of the treated subjects) produced a marked and statistically significant increase in the rate of regression of the precursor lesions (relative risks = 8.7 [95% CI = 2.7–28.2] for subjects with atrophy and 5.4 [95% CI = 1.7–17.6] for subjects with intestinal metaplasia). Conclusions: In the very high-risk population studied, effective anti-H. pylori treatment and dietary supplementation with antioxidant micronutrients may interfere with the precancerous process, mostly by increasing the rate of regression of cancer precursor lesions, and may be an effective strategy to prevent gastric carcinoma.

Expression and cellular localization of COX1 and -2 in Helicobacter pylori gastritis

Article

Feb 2001
ALIMENT PHARM THER

There are conflicting reports on the expression of cyclooxygenase in Helicobacter pylori infection. To evaluate the expression of COX-1 and COX-2 in H. pylori gastritis at messenger RNA (mRNA) and protein levels. Endoscopic gastric biopsies were obtained from patients with non-ulcer dyspepsia. The levels of COX-1 and COX-2 mRNA were compared between H. pylori-infected and uninfected specimens using reverse transcription-polymerase chain reaction. The immunohistochemical findings were correlated with the cellular localization of cyclooxygenase mRNA using in situ hybridization. A total of 40 H. pylori-infected and 40 uninfected specimens were studied. mRNA of COX-2 but not COX-1 was elevated in H. pylori-infected mucosa. COX-1 was localized to the mononuclear inflammatory, endothelial and smooth muscle cells in the lamina propria. COX-2 was barely detectable in uninfected mucosa but was strongly expressed in the foveolar and glandular epithelia in H. pylori gastritis. Cyclooxygenase-1 is expressed in the mononuclear inflammatory, endothelial and smooth muscle cells in the lamina propria irrespective of the H. pylori status. By contrast, H. pylori induces COX-2 expression in the foveolar and glandular epithelia.

Atrophy and Intestinal Metaplasia One Year After Cure of H. pylori Infection: A Prospective, Randomized Study

Article

Aug 2000
GASTROENTEROLOGY

Background & aims: Helicobacter pylori-infected gastric mucosa evolves through stages of chronic gastritis, intestinal metaplasia (IM), glandular atrophy (GA), and dysplasia before carcinoma develops. We studied if H. pylori eradication would alter the course of premalignant histologic changes in the stomach. Methods: Volunteers from the Yantai County in China underwent upper endoscopy with biopsy specimens obtained from the antrum and corpus. H. pylori-infected subjects were randomized to receive either a 1-week course of omeprazole, amoxicillin, and clarithromycin (OAC) or placebo. At 1 year, endoscopies with biopsies were repeated. Results: A total of 587 H. pylori-infected subjects were randomized to OAC (n = 295) and placebo (n = 292). At 1 year, H. pylori was eradicated in 226 subjects assigned to OAC. In the placebo group, 245 patients remained H. pylori infected. Analysis of paired samples obtained from the same patients showed that acute and chronic gastritis decreased in both the antrum and corpus after H. pylori eradication (P<0.001) and activity of IM decreased in antrum (P = 0.014). In the H. pylori-infected group, antral biopsy specimens had more pronounced acute gastritis (P = 0.01), whereas corpus specimens showed increased acute and chronic gastritis (P<0.001) and a marginal increase in GA (P = 0.052). When histologic changes were compared between the 2 groups, decrease in acute and chronic gastritis was more frequent after H. pylori eradication (P<0.001) but changes in IM were similar. In the H. pylori-infected group, increase in GA was seen in the corpus (P = 0.01). Conclusions: At 1 year, H. pylori eradication is beneficial in preventing progression of pathologic changes of the gastric mucosa.

Celecoxib, a selective cyclo-oxygenase-2 inhibitor reduces the severity of experimental colitis induced by dinitrobenzene sulfonic acid in rats

Article

Dec 2001
EUR J PHARMACOL

Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leukocyte infiltration, upregulation of the expression of intercellular adhesion molecule 1 (ICAM-1) and upregulation of P-selectin in the colon. Here, we investigate the effects of the selective cyclo-oxygenase-2 inhibitor, celecoxib, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced hemorrhagic diarrhoea and weight loss. At 4 days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology, as well as an increase in myeloperoxidase activity in the mucosa) was associated with upregulation of ICAM-1 and P-selectin, as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polymerase showed intense staining in the inflamed colon. Celecoxib (5 mg/kg twice a day orally) significantly reduced the degree of hemorrhagic diarrhoea and the weight loss caused by administration of DNBS. Celecoxib also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde, (iv) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (v) the upregulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that a selective cyclo-oxygenase-2 inhibitor celecoxib reduces the degree of colitis caused by DNBS.

Induction of Intestinal Metaplasia in the Stomachs of Rats by N-Methyl-N′-nitro-N-nitrosoguanidine2

Article

Aug 1978

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) was administered orally to male Wistar rats at a concentration of 83 microgram/ml in the drinking water for 2, 4, 5, and 7 months; the rats were killed at about month 15. Intestinal metaplasia was found in the stomachs of 80-100% of the rats treated with MNNG for 4 or more months, of 37.5% treated with MNNG for 2 months, and of 10% of the controls. Metaplastic glands, composed of goblet cells and columnar cells with striated borders, were found in the pyloric region. Paneth's cells were found at the bottom of metaplastic glands in a rat treated with MNNG for 4 months. The incidence of well-differentiated adenocarcinomas of the stomach was 63-90% in rats treated with MNNG for 4 or more months and 25% in those treated with MNNG for 2 months.

Tatematsu M, Takahashi M, Fukushima S, Hananouchi M, Shirai TEffects in rats of salt on experimental gastric cancers induced by N-methyl-N-nitro-N-nitrosoguanidine or 4-nitroquinoline-1-oxide. J Natl Cancer Inst 55: 101-106

Article

Aug 1975

The effects were studied of NaCl on the production of gastric carcinomas by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and by 4-nitroquinoline-1-oxide (NQO) in male Wistar rats. Nine groups of rats were treated as follows: Group 1 was given 50 mg MNNG/liter and 6 g NaCl solution/liter to drink and was fed a stock diet supplemented with 10% NaCl. Group 2 received 1 ml saturated NaCl once a week and 50 mg MNNG/liter to drink. Group 3 was treated with MNNG alone. Group 4 was given a solution of 1 mg NQO once a week and fed a stock diet supplemented with 10% NaCl. Group 5 received a solution of 1 mg NQO saturated with NaCl. Group 6 was given NQO alone. Groups 7 and 8 were given NaCl alone. Group 9 was untreated. Adenocarcinomas developed in the glandular stomach in group 2 at a significantly higher incidence than in group 3. Poorly differentiated adenocarcinomas of the glandular stomach were detected in only groups 1 and 2. One poorly differentiated adenocarcinoma metastasized to the lymph nodes. A high incidence of squamous cell carcinomas of the forestomach was found in groups 4 and 5. No malignant tumors were seen in groups 6-9. NaCl given alone had no apparent carcinogenicity in rats but, when administered with MNNG or NQO, it enhanced the carcinogenic effects of MNNG and NQO in the stomach.

Tumor Production in the Glandular Stomach and Alimentary Tract of the Rat by N-Methyl-N′-nitro-N-nitrosoguanidine

Article

Mar 1970

Genetic Control of Susceptibility of Rats to Gastric Carcinoma

Article

Sep 1983

Genetic control of the induction of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was studied in susceptible ACI rats, resistant Buffalo rats, and their F1 and F2 offspring. Both sexes of all strains, initially 7 to 9 weeks old, were given MNNG at a concentration of 83 micrograms/ml in their drinking water for 32 weeks and were sacrificed at experimental Week 72. The incidence of gastric adenocarcinoma in ACI rats was 80% in males and 47% in females; in Buffalo rats, the incidence was 18% in males and 0% in females. F1 hybrids showed the same resistance to MNNG as did Buffalo rats; the incidence of gastric adenocarcinoma was 17% in males and 8% in females. These results suggest that resistance to induction of gastric adenocarcinoma by MNNG is a dominant characteristic. The incidence of gastric adenocarcinoma in the F2 generation was 36% in males and 14% in females, which is close to the 3:1 ratio expected from the segregation of a single resistant gene. In ACI and Buffalo strains and their hybrids, males were more susceptible than females to induction of gastric carcinoma by MNNG. Intestinal tumors were observed mainly in the duodenum and jejunum in both strains and their hybrids, and the incidences were as follows: ACI: males, 67% and females 42%; Buffalo: males, 12% and females, 18%; F1: males, 18% and females, 15%; and F2: males, 15% and females, 19%. Thus, there seems to be a common genetic basis for both gastric and intestinal carcinogenesis by MNNG.

Sulindac and indomethacin inhibit formation of aberant crypt foci in the colons of dimethyl hydrazine treated rats

Article

Feb 1996

Aberrant crypt foci are microscopic lesions found in the colons of rodents treated with carcinogens, and in patients with premalignant colorectal conditions. They consist of single or multiple abnormal crypts and show cellular changes ranging from dysplasia to microscopic adenomacarcinoma. It is thought that these lesions represent the initial stages of the adenomacarcinoma path that results in the development of colorectal neoplasia. We have examined the effect of sulindac and indomethacin on the formation of aberrant crypt foci in rats treated with dimethylhydrazine (DMH). Aberrant crypt foci were induced in male Sprague-Dawley rats with two oral doses of dimethyl hydrazine at 25 mg/kg per dose. Rats were randomized to receive sulindac at 3 mg/kg (n = 20) or 10 mg/kg (n = 18) b.d., indomethacin at 1 mg/kg per day (n = 18) or 2 mg/kg per day (n = 19) or control (n = 37). Drug treatment was started on the day following the first dose of carcinogen and continued for 3 weeks. Colons were fixed flat overnight in 10% formalin and stained with 0.2%. Methylene Blue solution before being studied. There was a significant reduction in the number of aberrant crypt foci in rats treated with 10 mg/kg b.d., sulindac (P = 0.001) and indomethacin at 2 mg/kg per day (P = 0.0002). Sulindac, at 3 mg/kg b.d., and indomethacin, at 1 mg/kg per day, did not have a statistically significant effect (P = 0.089 and P = 0.052, respectively). None of the drug treatments affected the relative frequency of single crypt vs multiple crypt foci. Previous studies have shown that sulindac and indomethacin will significantly inhibit the growth and development of tumours in DMH treated rats. The current data suggest that one of the pathways of action of NSAID is to inhibit the formation of early preneoplastic lesions.

Evidence for involvement of cyclooxygenase-2 in proliferation of two gastrointestinal cancer cell lines

Article

Oct 1996
PROSTAG LEUKOTR ESS

Cyclooxygenase (COX) consists of two isozymes, COX-1 and COX-2. The roles of these isozymes in the gastrointestinal tract are unknown. We investigated messenger RNA expression of the COX-1 and COX-2 genes in the gastrointestinal cancer cell lines MKN28, MKN45, KATO III CACO-2, DLD-1 and LoVo. These cell lines expressed comparable levels of COX-1 mRNA, although their expression of COX-2 varied. Therefore, we studied the effects of NS-398 and indomethacin, specific and non-specific inhibitors for COX-2, on proliferation of the cell lines. Both of the inhibitors suppressed proliferation of the two cell lines that highly expressed COX-2 (MKN45 and CACO-2). However, these inhibitors exerted minimal effects on proliferation of the other cell lines, which expressed significantly lower levels of COX-2. Therefore, it was proposed that COX-2 participates in proliferation of cancer cells because of over expression of the COX-2 gene.

Expression of cyclooxygenase-2 in human gastric carcinoma

Article

May 1997

Epidemiological studies suggest that the use of aspirin decreases the incidence of and mortality from gastrointestinal cancers. The best known target of aspirin and other nonsteroidal anti-inflammatory drugs is cyclooxygenase (Cox), the rate-limiting enzyme in the conversion of arachidonic acid to prostanoids. Two Cox genes have been cloned, of which Cox-2 is an inducible immediate-early gene. It is still unknown how nonsteroidal anti-inflammatory drugs act as chemopreventive agents, but they may target Cox-2. Cox-2 mRNA and protein were recently found to be expressed in human colon carcinoma. We have now studied the expression of Cox-2 in human gastric adenocarcinoma tissues which contained significantly higher levels of Cox-2 mRNA when compared with paired gastric mucosal specimens devoid of cancer cells. In contrast, Cox-1 mRNA levels were not elevated in the carcinoma. However, Cox-2 mRNA was not expressed in mucinous ovarian carcinoma samples as detected by Northern blot hybridization. Immunohistological detection of Cox-2 protein showed cytoplasmic staining in the gastric carcinoma cells but not in the surrounding stroma. Some hyperplastic glands showed intense staining, whereas glands of normal morphology were negative. Our data thus suggest that Cox-2 is expressed by human gastric adenocarcinoma.

Aspirin use and colorectal cancer: Post-trial follow-up data from the Physicians' Health Study

Article

Jun 1998

In contrast to most observational studies, the randomized Physicians' Health Study found no association between aspirin use and colorectal cancer after 5 years. To determine the effect of randomly assigned aspirin treatment and self-selected aspirin use on the incidence of colorectal cancer after 12 years and to identify factors influencing the self-selection of regular aspirin use. Design: Randomized clinical trial and prospective cohort study. Male physicians throughout the United States. Patients: 22071 healthy male physicians who were 40 to 84 years of age in 1982. 325 mg of aspirin every other day. In 1988, the aspirin arm of the randomized trial was stopped early. Participants then chose to receive either aspirin or placebo for the rest of the study. Annual questionnaires asking about aspirin use and other variables, including occurrence of cancer. Colorectal cancer was diagnosed in 341 patients during the study period. Over 12 years of follow-up, random assignment to aspirin was associated with a relative risk for colorectal cancer of 1.03 (95% CI, 0.83 to 1.28). Various gastrointestinal symptoms and diagnoses were strong predictors of less frequent aspirin use in 1988. The relative risk for colorectal cancer in persons who used aspirin frequently after 1988 was 1.07 (CI, 0.75 to 1.53). In the Physicians' Health Study, both randomized and observational analyses indicate that there is no association between the use of aspirin and the incidence of colorectal cancer. The low dose of aspirin used and the short treatment period may account for the null findings. However, other characteristics associated with the use of aspirin in observational studies remain a plausible alternative explanation.

Cyclooxygenase-2 inhibitors supress the growth of gastric cancer xenografts via induction of apoptosis in nude mice

Article

Jul 1998
Am J Physiol

To clarify the role of mitogen-inducible cyclooxygenase (COX-2) in the development of malignant tumors, we investigated the effects of COX-2 inhibitors on the growth of gastric cancer xenografts in nude mice in vivo. MKN45 gastric cancer cells (5 x 10(6) cells/animal) that overexpress COX-2 were inoculated subcutaneously into athymic mice. NS-398, a specific COX-2 inhibitor, or indomethacin, a nonspecific COX-2 inhibitor, was administered orally to animals every day for 20 days. These drugs reduced the tumor volume significantly. Immunohistochemistry using bromodeoxyuridine, nick end labeling, and electron microscopy showed that NS-398 induced apoptosis in cancer cells in a dose-dependent manner and inhibited cancer cell replication slightly. Indomethacin also induced apoptosis and suppressed replication of tumor cells. There was a significant negative correlation between tumor volume and apoptotic cell number within the tumor. These results are consistent with the hypothesis that COX-2 inhibitors suppress growth of gastric cancer xenografts mainly by inducing apoptosis and suppressing replication of the neoplastic cells. It follows that COX-2 plays an important role in the development of gastric cancer.

Helicobacter pylori infection induces gastric cancer in Mongolian Gerbils

Article

Sep 1998
GASTROENTEROLOGY

Although epidemiological studies have indicated that Helicobacter pylori infection plays a crucial role in gastric carcinogenesis in humans, there is no direct proof that H. pylori is actually associated with gastric carcinogenesis. The purpose of this study was to elucidate the relationship between H. pylori infection and gastric carcinogenesis using an animal model of long-term H. pylori infection. Mongolian gerbils were orally inoculated with H. pylori, and the sequential morphological changes in the stomach were examined for up to 62 weeks. H. pylori was constantly detected in all infected animals throughout the study. At the 26th week, severe active chronic gastritis, ulcers, and intestinal metaplasia could be observed in infected animals. By the end of the study, adenocarcinoma had developed in the pyloric region of 37% of the infected animals. All tumors consisted of well-differentiated intestinal-type epithelium, and their development seemed to be closely related to intestinal metaplasia. We have successfully demonstrated that long-term infection with H. pylori induces adenocarcinoma in Mongolian gerbils. The observations are thus highly suggestive of the involvement of H. pylori infection in gastric carcinogenesis in humans.

The anti-inflammatory agents aspirin and salicylate inhibit the activity of I??B kinase-B

Article

Dec 1998

NF-kappaB comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response. NF-kappaB is sequestered in the cytoplasm by inhibitory proteins, I(kappa)B, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-alpha and IKK-beta, which phosphorylate I(kappa)B, leading to its degradation and translocation of NF-kappaB to the nucleus. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-alpha or by overexpression of the cellular kinases MEKK1 and NIK. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK-beta activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-beta to reduce ATP binding. Our results indicate that the anti-inflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappaB of genes involved in the pathogenesis of the inflammatory response.

Attenuation by genistein of sodium-chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats

Article

Feb 1999

The effects of prolonged administration of genistein, a tyrosine-kinase inhibitor, on sodium-chloride-enhanced induction of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labeling and apoptotic indices and vessel counts in the gastric mucosa and gastric cancers, were investigated in Wistar rats. After 25 weeks of the carcinogen treatment, rats were fed chow pellets containing 10% sodium chloride and were given s.c. injections of genistein at dosages of 15 mg/kg or 30 mg/kg body weight every other day. In week 52, the incidence of gastric cancers was significantly greater in rats fed sodium chloride than in untreated control rats. Prolonged administration of genistein at a dosage of 30 mg/kg, but not 15 mg/kg, body weight significantly reduced the incidence of gastric cancers, which was increased by oral treatment with sodium chloride. Genistein at the higher dose significantly decreased the labeling index and vessel counts of the antral mucosa and the gastric cancers (which were increased by treatment with sodium chloride) and significantly increased the apoptotic index of the antral mucosa and the cancers (which was lowered by the treatment with sodium chloride). These findings suggest that genistein attenuates gastric carcinogenesis promoted by sodium chloride, by inducing increased apoptosis and lower cell proliferation and angiogenesis of antral mucosa and gastric cancers.

Overexpression of Cyclooxygenase-2 protein is less frequent in gastric cancers with microsatellite instability

Article

Aug 1999

Overexpression of cyclooxygenase-2 (COX-2) has been reported in gastric cancers. However, the relationship between expression of COX-2 and clinico-pathological or genotypic features has not been elucidated. To address the issue, expression of COX-2 protein was analyzed in 100 gastric cancers as well as 7 gastric cancer cell lines by using immunoblot analysis. Overexpression of COX-2 in cancer tissues compared with matched non-cancerous tissues was found in 70% of cases and was significantly associated with lymphatic involvement, lymph node metastasis and advanced tumor stage. Interestingly, overexpression of COX-2 was less frequent in gastric cancers with microsatellite instability (MSI) than in those without MSI (8/20 vs. 62/80, p < 0.01). Expression of COX-2 protein was detected in some gastric cancer cell lines without MSI at various levels, but not in those with MSI. Our results suggest that overexpression of COX-2 may play an important role in tumor progression of gastric cancer and also support the notion that gastric cancers with and without MSI represent distinctive pathways of carcinogenesis. We also observed a reduction of MSI phenotype after aspirin or sulindac treatment in a hMLH1-defective gastric cancer cell line SNU-1, which lacks COX-2 expression. Int. J. Cancer (Pred. Oncol.) 84:400-403, 1999.

Pisani P, Parkin DM, Bray F, Ferlay J (1999a) Erratum: estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer, 83, 18-29. Int J Cancer 83: 870-873

Article

Oct 1999

We present here worldwide estimates of annual mortality from all cancers and for 25 specific cancer sites around 1990. Crude and age-standardised mortality rates and numbers of deaths were computed for 23 geographical areas. Of the estimated 5.2 million deaths from cancer (excluding non-melanoma skin cancer), 55% (2.8 million) occurred in developing countries. The sex ratio is 1.33 (M:F), greater than that of incidence (1.13) due to the more favourable prognosis of cancer in women. Lung cancer is still the most common cause of death from cancer worldwide with over 900,000 deaths per year, followed by gastric cancer with over 600,000 deaths and colorectal and liver cancers accounting for at least 400,000 deaths each. In men, deaths from liver cancer exceed those due to colo-rectal cancer by 38%. Over 300,000 deaths of women are attributed to breast cancer, which remains the leading cause of death from cancer in women, followed by cancers of the stomach and lung with 230,000 annual deaths each. In men, the risk of dying from cancer is highest in eastern Europe, with an age-standardised rate for all sites of 205 deaths per 100,000 population. Mortality rates in all other developed regions are around 180. The only developing area with an overall rate of the same magnitude as that in developed countries is southern Africa. All of eastern Asia, including China, has mortality rates above the world average, as do all developed countries. The region of highest risk among women is northern Europe (age-standardised rate = 125.4), followed by North America, southern Africa and tropical South America. Only south-central and western Asia (Indian subcontinent, central Asia and the middle-eastern countries) and Northern Africa are well below the world average of 90 deaths per 100,000 population annually. Our results indicate the potential impact of preventive practices. It is estimated that 20% of all cancer deaths (1 million) could be prevented by eliminating tobacco smoking. Infectious agents account for a further 16% of deaths.

Inhibition by rat C-erbB-2/neu antisense oligonucleotide of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats

Article

Dec 1999

The effect of prolonged administration of a rat C-erbB-2/neu (C-erbB-2) antisense oligonucleotide on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on the labeling and apoptotic indices of gastric cancer was examined in Wistar rats After oral treatment with MNNG for 25 weeks, the rats received intraperitoneal injections of a C-erbB-2 antisense-liposome complex or a sense-liposome complex at a dose of 50 microgram oligonucleotide/kg body weight every other day until the end of the experiment in week 52. In week 52, the incidence of gastric cancers was significantly lover in rats treated with the C-erbB-2 antisense oligonucleotide than in rats treated with the sense oligonucleotide. Administration of the C-erbB-2 antisense oligonucleotide also significantly decreased the bromodeoxyuridine-labeling index and significantly increased the apoptotic index of gastric cancers. The mean cellular fluorescence of gastric antral cells in MNNG-treated rats was positively correlated with the dose of FITC-labeled C-erbB-2 antisense oligonucleotide. Our findings indicate that the antisense oligonucleotide inhibits gastric carcinogenesis through decreased cell proliferation and increased apoptosis induction and suggest that antisense strategies may provide new treatment for gastric cancer.

Cyclooxygenase-2 expression is related to prostaglandin biosynthesis and angiogenesis in human gastric cancer

Article

Jan 2000

Although recent studies have demonstrated that cyclooxygenase (COX)-2 is overexpressed in various cancers including gastric cancer, the mechanisms underlying the contribution of COX-2 to tumorigenesis and tumor promotion still remain unclear. To determine the role of COX-2, we investigated the COX-2 expression, the prostaglandin (PG) levels, and the microvessel density in 42 patients with primary gastric adenocarcinoma. COX-2 protein was over-expressed in 31 (74%) of 42 gastric cancers based on an immunoblot analysis. The intensity of COX-2 expression was found to significantly correlate with lymph node involvement. The COX-2 overexpressed cases showed significantly elevated levels of prostaglandin E2 (PGE2) in cancer tissues in comparison with the normal gastric mucosa by an immunoassay (201 +/- 90 versus 161 +/- 57 ng/mg protein; P < 0.05). However, the COX-2 overexpression was not related to the levels of thromboxane B2 and 6-keto-prostaglandin F1alpha. The density of microvessel immunostained with CD34 was significantly higher in patients demonstrating COX-2 overexpression than in those without such expression (63 +/-21 versus 45 +/- 17/200 x; P < 0.01). Our data thus suggested COX-2 overexpression to be associated with increased PGE2 biosynthesis and angiogenesis in gastric cancer, which indicates that COX-2 may play a role in the development of gastric cancer.

Cyclooxygenase-2 Expression in Helicobacter pylori-Associated Premalignant and Malignant Gastric Lesions

Article

Oct 2000

Expression of cyclooxygenase-2 (COX-2) in various stages of the Helicobacter pylori-associated gastric carcinogenesis pathway has not been elucidated. We investigated the distribution and intensity of COX-2 expression in premalignant and malignant gastric lesions, and monitored the changes after H. pylori eradication. Gastric biopsies from H. pylori-infected patients with chronic active gastritis, gastric atrophy, intestinal metaplasia (IM), gastric adenocarcinoma, and noninfected controls were studied. Expression of COX-2 was evaluated by immunohistochemistry and in situ hybridization. Endoscopic biopsies were repeated 1 year after successful eradication of H. pylori in a group of IM patients for comparing COX-2 expression and progression of IM. In all H. pylori-infected patients, COX-2 expression was predominantly found in the foveolar and glandular epithelium and, to a lesser extent, in the lamina propria. In the noninfected group, only 35% of cases demonstrated weak COX-2 expression. Intensity of COX-2 was not significantly different between the chronic active gastritis, gastric atrophy, IM, and gastric adenocarcinoma groups. In 17 patients with IM, COX-2 expressions in the epithelial cells and stromal cells were reduced 1 year after H. pylori eradication. However, the changes in COX-2 expression did not correlate with progression/regression of IM. Both premalignant and malignant gastric lesions demonstrate strong COX-2 expression. Successful eradication of H. pylori leads to down-regulation of COX-2 expression but failed to reverse IM at 1 year.

Role of cyclooxygenase-2 in Helicobacter pylori-induced gastritis in Mongolian gerbils

Article

Nov 2000

Cyclooxygenase (COX)-2 expression is induced in the gastric mucosa of Helicobacter pylori-infected patients, but its role remains unclear. We examined the effects of NS-398 and indomethacin on gastric pathology in H. pylori-infected Mongolian gerbils. COX-1 was detected in both normal and H. pylori-infected mucosa, whereas COX-2 was expressed only in the infected mucosa. PGE(2) production was elevated by H. pylori infection, and the increased production was reduced by NS-398, which did not affect PGE(2) production in normal mucosa. Indomethacin inhibited PGE(2) production in both normal and infected mucosa. Hemorrhagic erosions, neutrophil infiltration, lymphoid follicles, and epithelium damage were induced by H. pylori infection. NS-398 and indomethacin aggravated these pathological changes but did not increase viable H. pylori number. H. pylori-increased production of neutrophil chemokine and interferon-gamma was potentiated by NS-398 and indomethacin. Neither NS-398 nor indomethacin caused any pathological changes or cytokine production in normal animals. These results indicate that COX-2 as well as COX-1 might play anti-inflammatory roles in H. pylori-induced gastritis.

Expression and cellular localization of COX-1 and -2 in Helicobacter pylori gastritis

Article

Mar 2001

Sequential Morphological Changes in N-Methyl-N′-Nitro-N-Nitrosoguanidine Carcinogenesis in the Glandular Stomach of Rats

Article

May 1970

Chemopreventive effects of curcumin on glandular stomach carcinogenesis induced by N-methyl-N′-nitro-N-nitrosoguanidine and sodium chloride in rats

Article

Sep 2001

The modifying effects of pure curcumin on glandular stomach carcinogenesis were investigated during the post-initiation phase in male Wistar rats treated with N-methyl-N'-nitro-N-nitrosoguanisine (MNNG) and sodium chloride. A total of 110 male 6-week-old rats were divided into four groups. Groups 1-3 (consisting of 30 rats/group) were given MNNG in their drinking water at a concentration of 100 ppm and simultaneously fed a diet supplemented with 5% NaCl for 8 weeks. They were then fed a diet containing either 0.2% (group 1) or 0.05% (group 2) pure curcumin or kept on a basal diet alone (group 3) for 55 weeks. The rats of the curcumin-treated groups (groups 1 and 2) were then switched to the basal diet for the following 4 weeks before sacrifice. Group 4 (20 rats) served as a non-treatment control. The total incidence of combined atypical hyperplasias and adenocarcinomas in the glandular stomachs was rather lower in groups 1 (93%) and 2 (90%) than in group 3 (100%), albeit without statistical significance. However, the mean number of atypical hyperplasias or adenocarcinomas of the glandular stomachs in group 1 (4.70) was significantly less than the value of group 3 (7.17) (p<0.05). Thus, the development of cancerous and precancerous lesions in the glandular stomach was decreased by exposure to pure curcumin. The present results indicate that the compound exerts chemopreventive effects, when given during the post-initiation phase of glandular stomach carcinogenesis in rats.

Gupta RA, Dubois RNColorectal cancer prevention and treatment by inhibition of Cox-2. Nature Rev Cancer 1: 11-21

Article

Nov 2001
NAT REV CANCER

Population-based studies have established that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), reduces the relative risk for developing colorectal cancer. These studies led to the identification of a molecular target, COX-2, that is involved in tumour promotion during colorectal cancer progression. Recent studies in humans indicate that therapy with specific COX-2 inhibitors might be an effective approach to colorectal cancer prevention and treatment.

Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention

Article

Apr 2002
LANCET ONCOL

Timothy A. Chan

Nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit colorectal tumorigenesis and are among the few agents known to be chemopreventive. Epidemiological studies and experiments with animals have shown that NSAIDs have powerful anticolorectal cancer properties, but the mechanism of these effects remains unclear. NSAIDs can inhibit neoplastic growth by inducing apoptosis in cancer cells; the way they do this is currently an area of intense investigation. The most well-characterised pharmacological feature of NSAIDs is their inhibition of the enzyme cyclo-oxygenase (COX), which catalyses the synthesis of prostaglandins. Several studies have shown that COX inhibition prevents cell proliferation and promotes apoptosis. The chemopreventive effects of NSAIDs are thought to occur via this pathway. Other observations indicate that NSAIDs also promote apoptosis through mechanisms that are independent of COX inhibition. This idea is supported by the finding that compounds that are structurally similar to NSAIDs, but do not inhibit COX, also have chemopreventive and proapoptotic properties. COX-dependent and COX-independent mechanisms of apoptosis induction are not mutually exclusive, and it is likely that both have a role in the biological activity of NSAIDs. Knowledge of how NSAIDs prevent neoplastic growth will greatly aid the design of better chemopreventive drugs and novel treatments for colorectal cancer.

Karin M, Cao Y, Greten FR and Li ZWNF-kappaB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer 2: 301-310

Article

May 2002
NAT REV CANCER

Nuclear factor of kappaB (NF-kappaB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-KB in immunity is undisputed, recent evidence indicates that NF-kappaB and the signalling pathways that are involved in its activation are also important for tumour development. NF-kappaB should therefore receive as much attention from cancer researchers as it has already from immunologists.

Cyclooxygenase-2 and Bcl-2 expression in the stomach mucosa of Wistar rats exposed to Helicobacter pylori, N′-methyl-N′-nitro-N-nitrosoguanidine and bile

Article

Aug 2002

Cyclooxygenase-2 (COX-2) and Bcl-2 have been implicated in upper gastrointestinal tract carcinomas, but the underlying mechanisms are not known. In the present study we assessed the correlation of COX-2 and Bcl-2 to known cell kinetics in the glandular stomach mucosa of 104 Wistar rats given combinations of Helicobacter pylori, MNNG ( N'-methyl- N'-nitro- N-nitrosoguanidine) and bile. COX-2 expression, Bcl-2 and cell proliferation (Ki-67) in antral and corpus mucosa were determined immunohistochemically. Apoptotic cells were detected using terminal uridine deoxynucleotidyl nick end labelling technique. Expression of COX-2 was found in the lower portion of glandular corpus epithelium, and Bcl-2 positivity was mainly seen in the proliferative zone of both antrum and corpus mucosa. COX-2 expression in histologically normal-appearing corpus mucosa was associated with cell proliferation, atrophy and intestinal metaplasia in antrum and with Bcl-2 expression in corpus mucosa. No correlation was found between apoptosis and Bcl-2 expression. MNNG but not H. pylori significantly increased COX-2 in corpus mucosa. H. pylori, however, promoted the COX-2 expression in corpus when bile was added and Bcl-2 expression in antrum. Abnormal expression of both COX-2 and Bcl-2 seem to be involved in H. pylori-induced gastric carcinogenesis by altering the gastric cell kinetics.

Effect of the selective COX-2 inhibitors, celecoxib and rofecoxib in rat acute models of inflammation

Article

Jan 2003

This study evaluates the action of celecoxib and rofecoxib, two selective cyclooxygenase-2 (COX-2) inhibitors in two acute models of inflammation, carrageenan (Cg)-induced rat pleurisy, and paw oedema formation. Male Wistar rats (N = 4-10 per group) were used. A fixed volume of PBS or carrageenan was injected into the pleural cavity or into the paw. Furthermore, the myeloperoxidase (MPO) activity and the levels of nitrite/nitrate (NOx), interleukin-1beta (IL-1beta), tumor necrosis factor-a (TNF-a) and PGE2 were also assessed in the paw tissue or in pleural exudate. Dexamethasone (DEX, 0.5 mg kg(-1), s.c., -4 h) and indomethacin (INDO, 3 mg kg(-1), p.o., -1 h) suppressed Cg-induced pleural exudate accumulation by 84 and 77% and inflammatory cell influx by 66 and 47%, respectively. In contrast, celecoxib (CLX, 10 mg kg(-1), p.o., -1 h) or rofecoxib (RFX, 10 mg kg(-1) , p.o., -1 h) only reduced the Cg-induced pleural exudate volume by 44 and 40%, respectively, but had no significant effect over inflammatory cell influx. At the same doses used for pleurisy, DEX, INDO, CLX, RFX and SC-560 (a selective COX-1 inhibitor, 40 mg kg(-1), p.o., -1 h), inhibited the Cg-induced paw oedema by 49, 31, 21, 21 and 17%. DEX, INDO or SC-560 reduced the level of MPO by 71, 78 and 59%, while CLX or RFX produced a small, but significant increase (28 or 16%) in MPO activity. In the rat model of pleurisy, PGE2 levels in cell-free exudates were significantly attenuated by 91, 89, 57 and 65% in animals treated with DEX, INDO, CLX or RFX. In contrast, INDO reduced significantly the whole bloodTXB, synthesis (59%) while DEX and INDO reduced the pleural content of NOx significantly. Treatment of animals with CLX or RFX did not alter the content of pro-inflammatory cytokines IL-1beta or TNF-alpha in the pleural exudate, but CLX reduced IL-1beta levels in the rat paw tissue and RFX increased TNF-alpha in this tissue. Together these results provide consistent evidence indicating that the selective COX-2 inhibitors CLX and RFX, in contrast to DEX, INDO or SC-560, despite reducing greatly the Cg-induced pleural exudation, PGE2 content and paw oedema have only partial acute anti-inflammatory properties in two different rat acute models of inflammation.

Celecoxib acts in a cyclooxygenase-2-independent manner and I synergy with emodin to suppress rat cholangiocarcinoma growth in vitro through a mechanism involving enhanced Akt inactivation and increases activation of caspases-9 and 3

Article

Apr 2003

Emodin, a tyrosine kinase inhibitor, effectively blocked tyrosine phosphorylation of p185(neu) overexpressed in cultured rat C611B cholangiocarcinoma (ChC) cells and in neu-transformed WB-F344 rat-liver epithelial stem-like cells (WBneu cells). Celecoxib, a cyclooxygenase-2 inhibitor, markedly decreased prostaglandin (PG) levels overproduced by these respective neoplastically transformed liver cell types but was without effect in inhibiting PG production by untransformed WB-F344 cells that do not express detectable cyclooxygenase-2 protein. Notably, in combination, emodin (30 micro M) and celecoxib (35 micro M) acted synergistically to significantly suppress anchorage-dependent and -independent growth of C611B ChC cells and of WBneu cells over treatments with either agent alone. This prominent suppression of cell growth correlated with significant increases in the activation of caspases-9 and -3 and induction of apoptosis in the combination-treated cells, which was associated with an enhanced suppression of Akt activation. Here it is important to note that the concentration of celecoxib needed to suppress growth and induce apoptosis in the C611B and WBneu cells was markedly higher than that needed to effectively inhibit PG production by these malignant cell types. Thus, our data indicate that celecoxib is acting independently of its ability to inhibit cyclooxygenase-2 activity in suppressing growth of C611B and WBneu cells in vitro. Furthermore, our findings strongly suggest that increased inhibition of the antiapoptotic kinase Akt activation produced by the emodin/celecoxib combination treatment plays a key role in the mechanism by which this drug combination acts to enhance cell growth suppression and apoptosis in cultured C611B ChC cells and WBneu cells.

Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions

Jan 2000

Jjy Sung
W K Leung
Myy Go

Estimates of the worldwide mortality from 25 cancers in 1990

Jan 1999

P Pisani
D M Parkin
F Bray

Sulindac and indomethacin inhibit formation of aberrant crypt foci in the colons of dimethyl hydrazine treated rats

Jan 1996

D Charalambous
C Farmer
O Brien

Colorectal cancer prevention and treatment by inhibition of cycloxoygenase-2

Jan 2001

R A Gupta
R N Dubois

Chemoprevention of gastric cancer by celecoxib in rats

Abstract

No full-text available

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