OBJECTIVETo test the effect of sulindac on autistic behaviors in a rat model and explore the possible mechanisms.

METHODSAutistic rat models were established by a single intraperitoneal injection of sodium valproate (VPA) at 12.5 days of pregnancy. The pregnant rats were treated with oral sulindac at a daily dose of 80 mg/kg until weaning of the newborn rats (23 days after being born), which were divided into control, VPA treatment, sulindac treatment, and VPA+ sulindac treatment groups. The social interaction and neuroethology of the newborn rats were evaluated at 35 days, and the levels of β-catenin and phosphorylated Gsk3β in the brain tissues were investigated by Western blotting.

RESULTSCompared with the control rats, the rats treated with VPA showed lower social interaction, longer moving time in central area, and reduced standing times. Treatment with sulindac alone resulted in no obvious changes in the social interaction or neuroethology of the newborn rats, but sulindac treatment corrected VPA-induced autistic-like behaviors. Sulindac also attenuated VPA-triggered p-Gsk3β downregulation and β-catenin upregulation in the prefrontal lobe, seahorse and cerebellum.

CONCLUSIONSulindac can improve the behaviors of autistic rats possibly by suppressing Wnt signaling pathway.

Animals ; Autistic Disorder ; drug therapy ; Disease Models, Animal ; Down-Regulation ; Female ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Prefrontal Cortex ; Pregnancy ; Rats ; Sulindac ; pharmacology ; Up-Regulation ; Valproic Acid ; Wnt Signaling Pathway ; beta Catenin ; metabolism

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) and statins are potential chemopreventive or chemotherapeutic agents. The mechanism underlying the deregulation of survivin by NSAIDs and statins in human non-small cell lung cancer cells has not been elucidated. In this study, we investigated the synergistic interaction of sulindac and simvastatin in lung cancer A549 cells. MATERIALS AND METHODS: Cell viability was measured by an MTT assay, while the expression of apoptotic markers, AKT, and survivin in response to sulindac and simvastatin was examined by Western blotting. DNA fragmentation by apoptosis was analyzed by flow cytometry in A549 cells. Reactive oxygen species (ROS) generation was measured by flow cytometry using H2DCFDA and MitoSOX Red, and the effects of pretreatment with N-acetylcysteine were tested. The effects of AKT on survivin expression in sulindac- and simvastatin-treated cells were assessed. Survivin was knocked down or overexpressed to determine its role in apoptosis induced by sulindac and simvastatin. RESULTS: Sulindac and simvastatin synergistically augmented apoptotic activity and intracellular ROS production in A549 cells. Inhibition of AKT by siRNA or LY294002 inhibited survivin, while AKT overexpression markedly increased survivin expression, even in the presence of sulindac and simvastatin. Moreover, survivin siRNA enhanced sulindac- and simvastatininduced apoptosis. In contrast, survivin upregulation protected against sulindac- and simvastatin-induced apoptosis. CONCLUSION: Combined treatment with sulindac and simvastatin augmented their apoptotic potential in lung cancer cells through AKT signaling-dependent downregulation of survivin. These results indicate that sulindac and simvastatin may be clinically promising therapies for the prevention of lung cancer.
Acetylcysteine ; Anti-Inflammatory Agents, Non-Steroidal ; Apoptosis* ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung ; Cell Survival ; DNA Fragmentation ; Down-Regulation* ; Flow Cytometry ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Lung Neoplasms* ; Oncogene Protein v-akt ; Reactive Oxygen Species ; RNA, Small Interfering ; Simvastatin* ; Sulindac* ; Up-Regulation

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by hundreds of colorectal adenomatous polyps that progress to colorectal cancer. Management of patients with FAP is with a total colectomy. Chemopreventive strategies have been studied in FAP patients in an effort to delay the development of adenomas in the upper and the lower gastrointestinal tract and to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery. Sulindac, a nonsteroidal anti-inflammatory drug, causes regression of colorectal adenomas in the retained rectal segment of FAP patients. However, evidence regarding long-term use of this therapy and its effect on the intact colon has been insufficient. We report a case in which the long-term use of sulindac was effective in reducing the size and the number of colonic polyps in patients with FAP without a prophylactic colectomy and polypectomy; we also present a review of the literature.
Adenoma* ; Adenomatous Polyposis Coli* ; Adenomatous Polyps ; Chemoprevention ; Colectomy* ; Colon* ; Colonic Polyps ; Colorectal Neoplasms ; Follow-Up Studies* ; Humans ; Lower Gastrointestinal Tract ; Rectum ; Recurrence ; Sulindac*

Attenuated familial adenomatous polyposis (AFAP) is a variant of familial adenomatous polyposis with fewer than one hundred colorectal polyps and a later age of onset of the cancer. Here, we report two cases of AFAP within family members. Each patient demonstrated the same novel germ line mutation in exon 15 of the adenomatous polyposis coli (APC) gene and was successfully managed with sulindac after refusal to perform colectomy: a 23-year-old man with incidentally diagnosed gastric adenoma and fundic gland polyps underwent colonoscopy, and fewer than 100 colorectal polyps were found; a 48-year-old woman who happened to be the mother of the 23-year-old man also showed fewer than 100 colorectal polyps on colonoscopy. Genetic analysis revealed a novel frameshift mutation in exon 15 of the APC gene. The deletion of adenine-guanine with the insertion of thymine in c.3833-3834 resulted in the formation of stop codon 1,287 in both patients. The patients were treated with sulindac due to their refusal to undergo colectomy. The annual follow-up upper endoscopy and colonoscopy in the following 2 years revealed significant regression of the colorectal polyps in both patients.
Adenoma ; Adenomatous Polyposis Coli ; Age of Onset ; Codon, Terminator ; Colectomy ; Colonoscopy ; Disulfiram ; Endoscopy ; Exons ; Female ; Follow-Up Studies ; Frameshift Mutation ; Genes, APC ; Germ-Line Mutation ; Humans ; Mothers ; Polyps ; Sulindac ; Thymine

PURPOSE: It is known that cyclooxygenase (COX)-2 expression is increased in Barrett's esophagus and esophageal adenocarcinomas. We studied COX-2 expression and the effect sulindac has on the genesis of Barrett's esophagus and adenocarcinoma in rats undergoing esophagogastroduodenal anastomosis (EGDA). MATERIALS AND METHODS: Fifty-one rats were divided into a control group (n=27), a 500ppm sulindac-treated group (n=15) and 1000 ppm sulindac-treated group (n=9). Randomly selected rats were killed by diethyl ether inhalation at 20 and 40 weeks after surgery. RESULTS: At 40 weeks, rats treated with 1000 ppm sulindac showed narrower esophageal diameter and milder inflammation than the control rats. At 40 weeks, the incidence of Barrett's esophagus was similar between control and sulindac-treated groups, but the incidence of adenocarcinoma was significantly lower in the 1000ppm sulindac-treated group than either the control or 500 ppm sulindac-treated groups. COX-2 was significantly increased in the lower esophagus of control rats killed at 40 weeks. Cyclin D1 expression was negligible in the sulindac- treated group compared with the control group. CONCLUSION: We suggest that the chemopreventive effect of sulindac is related to decreased COX-2 and cyclin D1 expression, which may be influenced by reduced inflammation.
Adenocarcinoma/etiology/metabolism/*prevention & control ; Animals ; Antineoplastic Agents/therapeutic use ; Barrett Esophagus/etiology/metabolism/prevention & control ; Blotting, Western ; Cyclin D1/metabolism ; Cyclooxygenase 2/metabolism ; Duodenogastric Reflux/*complications ; Esophageal Neoplasms/etiology/metabolism/*prevention & control ; Immunohistochemistry ; Male ; Proliferating Cell Nuclear Antigen/metabolism ; Rats ; Rats, Sprague-Dawley ; Sulindac/*therapeutic use

OBJECTIVETo investigate the effect of sulindac on proliferation and apoptosis of human gastric cancer BGC-823 cells and its antineoplastic mechanisms.

METHODSHuman gastric cancer BGC-823 cells were incubated with sulindac at various concentrations and for different times. Morphological changes of BGC-823 cells were observed under an inversion microscope. MTT colorimetric assay was used to examine the effect of sulindac on the proliferation of BGC-823 cells. Flow cytometry was used to determine the cell cycle distribution and apoptosis. Transmission electron microscopy was performed to examine cell apoptosis morphology. Immunohistochemical staining was used to detect the expressions of COX-2, bcl-2 and ki-67 in the cells.

RESULTSsulindac induced morphologic alterations in BGC-823 cells, inhibited cell proliferation, increased the proportion of cells in G0/G1 phase and decreased the proportion of cells in S phase, induced apoptosis of BGC-823 cells, and decreased expressions of COX-2, bcl-2, ki-67 in the cells. All the effects were in a time- and dose-dependent manner (P < 0.05). Some characteristic morphologic features of apoptosis were revealed by transmission electron microscopy.

CONCLUSIONsulindac may inhibit the growth of gastric cancer BGC-823 cells in vitro and the anti-tumor mechanism may be related to changes in cell cycle distribution, induction of apoptosis and inhibition of expression of COX-2, bcl-2, and ki-67.

Antineoplastic Agents ; administration & dosage ; pharmacology ; Apoptosis ; drug effects ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cyclooxygenase 2 ; metabolism ; Dose-Response Relationship, Drug ; Humans ; Ki-67 Antigen ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Stomach Neoplasms ; metabolism ; pathology ; Sulindac ; administration & dosage ; pharmacology

In patients with renal transplant failure's the graft can be left in situ when there are no additional complications. Graft intolerance occurs in some failed renal grafts when the immunological treatment is completely withdrawn. We experienced a case of graft intolerance syndrome in a patient with renal graft failure treated by percutaneous renal artery embolization. A 31 year -old man was admitted at nephrology department because of fever and hematuria without other infection focus. He was diagnosed as graft intolerance syndrome and treated by percutaneous embolization of the failed renal allograft. The embolization was successful. He suffered from post-emboization syndrome and treated by sulindac. We report this case with a review of relevant literatures and conclud that percutaneous renal artery embolizaion is a simple, safe and effective technique for the treatment of nonfunctioning renal allograft with clinical intolerance. Surgical nephrectomy should be reserved as a second level of treatment when allograft embolization has been ineffective owing to reappearance of manifestations of clinical intolerance.
Allografts ; Fever ; Hematuria ; Humans ; Nephrectomy ; Nephrology ; Renal Artery* ; Sulindac ; Transplants*

BACKGROUND: Arsenic trioxide (As2O3) has been used to treat acute promyelocytic leukemia, and it induces apoptosis in a variety of solid tumor cell lines including non-small cell lung cancer cells. However, nonsteroidal anti- inflammatory drugs (NSAID) can enhance tumor response to chemotherapeutic drugs or radiation. It was previously demonstrated that a combination treatment with As2O3 and sulindac induces the apoptosis of NCI-H157 human lung carcinoma cells by activating the caspase cascade. This study aimed to determine if a combination treatment augmented its apoptotic potential through other pathways except for the activation of the caspase cascade. MATERIAL AND METHODS: The NCI-H157 cells were treated with As2O3, sulindac and antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC). The cell viability was measured by a MTT assay, and the level of intracellular hydrogen peroxide (H2O2) generation was monitored fluorimetrically using a scopoletin-horse radish peroxidase (HRP) assay. Western blotting and mitochondrial membrane potential transition analysis were performed in order to define the mechanical basis of apoptosis. RESULTS: The viability of the cells was decreased by a combination treatment of As2O3 and sulindac, and the cells were protected using antioxidants in a dose-dependent manner. The increased H2O2 generation by the combination treatment was inhibited by antioxidants. The combination treatment induced changes in the mitochondrial tran-smembrane potential as well as the expression of the Bcl-2 family proteins, and increased cytochrome c release into the cytosol. However, the antioxidants inhibited the effects of the combination treatment. CONCLUSION: Combination treatment with As2O3 and sulindac induces apoptosis in NCI-H157 human lung carcinoma cells via ROS generation with a mitochondrial dysfunction.
Acetylcysteine ; Antioxidants ; Apoptosis* ; Arsenic* ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung ; Cell Line, Tumor ; Cell Survival ; Cytochromes c ; Cytosol ; Glutathione ; Humans* ; Hydrogen Peroxide ; Leukemia, Promyelocytic, Acute ; Lung* ; Membrane Potential, Mitochondrial ; Peroxidase ; Raphanus ; Sulindac*

PURPOSE: This study was undertaken to reveal the molecular mechanism underlying sulindac-induced apoptosis in the human colon cancer cell line HT-29 (mutant p53). METHODS: Apoptosis was determined by using Hoechst 33342 staining, and translocation of proteins was established by using immunofluorescence, immunoelectron microscopy, and Western blotting after ultra- fractionation. RESULTS: This type of apoptosis was associated with decreased mitochondrial membrane potential, a translocation of the apoptosis-inducing factor (AIF) to the nucleus, and morphological evidence of nuclear condensation. However, DNA electrophoresis did not elucidate the ladder pattern of DNA fragments. Instead, a pulse-field gel electrophoresis showed that sulindac led to disintegration of nuclear DNA into-high- molecular-weight DNA fragments of about 100~300 kbp. CONCLUSIONS: Our findings indicate that sulindac induces large-scale DNA fragmentation, suggesting a predominantly AIF-mediated cell-death process, through translocation of the AIF to the nucleus in HT-29 cells.
Apoptosis Inducing Factor ; Apoptosis* ; Blotting, Western ; Cell Line ; Colonic Neoplasms ; DNA Fragmentation* ; DNA* ; Electrophoresis ; Fluorescent Antibody Technique ; HT29 Cells* ; Humans ; Membrane Potential, Mitochondrial ; Microscopy, Immunoelectron ; Sulindac

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAID) are useful in chemoprevention of colorectal cancers. Continuous NSAID administation causes 40% to 50% reduction in relative risk for colorectal cancer. Sulindac possesses an antiproliferative effect and induces apoptosis and tumor regression on colon cancer and other types of cancers. We intended to analyze the effects of sulindac in three non-small cell lung cancer cell lines. MATERIALS AND METHODS: The human lung cancer cell lines, A549, NCI-H157 and NCI-H460 were used for this study. Viability was tested by MTT assay, and cell death rate was measured by lactate dehydrogenase(LDH) release. Apoptosis was estimated by flow cytometric analysis and nuclear staining. RESULTS: Sulindac was able to decrease the viability of non-small cell lung cancer cells in a dose- and time- dependent manner. In a parallel effect of sulindac on cell death rate, LDH release was increased in sulindac-treated lung cancer cells. Sulindac significantly increased apoptosis characterized by an increase of sub-G0/G1 fraction and morphological change of nuclei. The rate of apoptotic cells after sulindac treatment in lung cancer cells increased in a time- and dose- dependent manner in flow cytometric analysis. Apoptotic cells were defined as nuclear shrinkage, chromatin condensation and nuclear fragmentation of cells. CONCLUSION: Sulindac decreases viability and induces the apoptosis of lung cancer cells. Further studies will be needed to elucidate the potential mechanism of sulindac-induced apoptosis in lung cancer cells.
Apoptosis* ; Carcinoma, Non-Small-Cell Lung ; Cell Death ; Cell Line ; Chemoprevention ; Chromatin ; Colonic Neoplasms ; Colorectal Neoplasms ; Humans* ; Lactic Acid ; Lung Neoplasms* ; Lung* ; Sulindac*