sulindac and Carcinoma

Topics: Adenoma; Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Carcinoma; Celecoxib; Colorectal Neoplasms; Evidence-Based Medicine; Humans; Meta-Analysis as Topic; Pyrazoles; Sulfonamides; Sulindac

Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronectin-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.

Topics: Adenomatous Polyposis Coli Protein; beta Catenin; Brain Neoplasms; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dishevelled Proteins; Female; Fibronectins; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; Indazoles; Integrins; Matrix Metalloproteinase 7; Microscopy, Confocal; Microscopy, Fluorescence; Microscopy, Video; Mutation; Phenotype; RNA Interference; RNA, Small Interfering; Sulfonamides; Sulindac; Triple Negative Breast Neoplasms; Up-Regulation; Wnt Proteins; Wnt Signaling Pathway

Sulindac has anti-neoplastic properties against colorectal cancers; however, its use as a chemopreventive agent has been limited due to toxicity and efficacy concerns. Combinatorial treatment of colorectal cancers has been attempted to maximize anti-cancer efficacy with minimal side effects by administrating NSAIDs in combination with other inhibitory compounds or drugs such as l-ascorbic acid (vitamin C), which is known to exhibit cytotoxicity towards various cancer cells at high concentrations. In this study, we evaluated a combinatorial strategy utilizing sulindac and vitamin C. The death of HCT116 cells upon combination therapy occurred via a p53-mediated mechanism. The combination therapeutic resistance developed in isogenic p53 null HCT116 cells and siRNA-mediated p53 knockdown HCT116 cells, but the exogenous expression of p53 in p53 null isogenic cells resulted in the induction of cell death. In addition, we investigated an increased level of intracellular ROS (reactive oxygen species), which was preceded by p53 activation. The expression level of PUMA (p53-upregulated modulator of apoptosis), but not Bim, was significantly increased in HCT116 cells in response to the combination treatment. Taken together, our results demonstrate that combination therapy with sulindac and vitamin C could be a novel anti-cancer therapeutic strategy for p53 wild type colon cancers.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Ascorbic Acid; Carcinoma; Colonic Neoplasms; Combined Modality Therapy; Dietary Supplements; Drug Resistance, Neoplasm; Food-Drug Interactions; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Osmolar Concentration; Oxidants; Proto-Oncogene Proteins; Reactive Oxygen Species; RNA Interference; Sulindac; Tumor Suppressor Protein p53

Colorectal cancer (CRC) is a major cause of mortality in Western populations. Growing evidence from human and rodent studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) cause regression of existing colon tumors and act as effective chemopreventive agents in sporadic colon tumor formation. Although much is known about the action of the NSAID sulindac, especially its role in inducing apoptosis, mechanisms underlying these effects is poorly understood. In previous secretome-based proteomic studies using 2D-DIGE/MS and cytokine arrays we identified over 150 proteins released from the CRC cell line LIM1215 whose expression levels were dysregulated by treatment with 1mM sulindac over 16h; many of these proteins are implicated in molecular and cellular functions such as cell proliferation, differentiation, adhesion, angiogenesis and apoptosis (Ji et al., Proteomics Clin. Appl. 2009, 3, 433-451). We have extended these studies and describe here an improved protein/peptide separation strategy that facilitated the identification of 987 proteins and peptides released from LIM1215 cells following 1mM sulindac treatment for 8h preceding the onset of apoptosis. This peptidome separation strategy involved fractional centrifugal ultrafiltration of concentrated cell culture media (CM) using nominal molecular weight membrane filters (NMWL 30K, 3K and 1K). Proteins isolated in the >30K and 3-30K fractions were electrophoretically separated by SDS-PAGE and endogenous peptides in the 1-3K membrane filter were fractioned by RP-HPLC; isolated proteins and peptides were identified by nanoLC-MS-MS. Collectively, our data show that LIM1215 cells treated with 1mM sulindac for 8h secrete decreased levels of proteins associated with extracellular matrix remodeling (e.g., collagens, perlecan, syndecans, filamins, dyneins, metalloproteinases and endopeptidases), cell adhesion (e.g., cadherins, integrins, laminins) and mucosal maintenance (e.g., glycoprotein 340 and mucins 5AC, 6, and 13). A salient finding of this study was the increased proteolysis of cell surface proteins following treatment with sulindac for 8h (40% higher than from untreated LIM1215 cells); several of these endogenous peptides contained C-terminal amino acids from transmembrane domains indicative of regulated intramembrane proteolysis (RIP). Taken together these results indicate that during the early-stage onset of sulindac-induced apoptosis (evidenced by increased annexin V binding, dephosphorylati

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Carcinoma; Cell Line, Tumor; Colon; Colonic Neoplasms; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Humans; Proteolysis; Proteome; Proteomics; Secretory Pathway; Sulindac

Overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has emerged as a pivotal trigger of thyroid carcinogenesis. Recent findings from other tumor entities revealed that PI3K/Akt-driven carcinogenesis critically involves the inactivation of the tumor-suppressive transcription factor Forkhead box O (FOXO)-3. However, little is known about FOXO3 in the thyroid context.. We sought to investigate the influence of the thyroid oncogenes BRAFV600E, H-RASV12, and p110α (H1074R) on the regulation of the PI3K downstream target FOXO3 in vitro. Furthermore, the impact of the expression of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) on the transcriptional activity of FOXO3 was assessed in a panel of 44 human thyroid tumors. Finally, we tried to modulate FOXO3 activity pharmacologically with help of the nonsteroidal antiinflammatory drug sulindac sulfide (SS).. We found that the overexpression of p110α H1074R results in the inactivation of FOXO3 via its nuclear exclusion. In vivo, we observed a direct correlation between PTEN expression and the transcriptional activation of FOXO3. In vitro, we found that stimulation with SS reversed PI3K/Akt-driven inactivation of FOXO3, resulting in its nuclear relocation and a combined induction of the antiproliferative FOXO target genes Gadd45α and p27(kip1) and the proapoptotic FOXO target gene Bim in benign (FRTL-5) and malignant human thyrocytes (FTC-133). In agreement with this, SS promoted the cell cycle arrest and apoptosis in thyroid cells, which could be amplified by the transfection of exogenous FOXO3.. Our data suggest that deregulation of proapoptotic FOXO3 represents a central step in PI3K/Akt-mediated thyroid carcinogenesis. Thus, SS might represent an attractive pharmacological tool for targeting thyroid neoplasia with aberrant PI3K/Akt/FOXO3 signaling.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carcinoma; Forkhead Box Protein O3; Forkhead Transcription Factors; Humans; Oncogenes; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Sulindac; Thyroid Neoplasms; Tumor Cells, Cultured

Activation of the transcription factor nuclear factor-kappa B (NF-kappa B) has been implicated in pancreatic tumorigenesis. We evaluated the effect of a novel NF-kappa B inhibitor, parthenolide, a sesquiterpene lactone isolated from the herb feverfew, in three human pancreatic tumor cell lines (BxPC-3, PANC-1, and MIA PaCa-2). Parthenolide inhibited pancreatic cancer cell growth in a dose-dependent manner with substantial growth inhibition observed between 5 and 10 micromol/L parthenolide in all three cell lines. Parthenolide treatment also dose-dependently increased the amount of the NF-kappa B inhibitory protein, I kappa B-alpha, and decreased NF-kappa B DNA binding activity. We have previously shown that nonsteroidal anti-inflammatory drugs (NSAID) suppress the growth of pancreatic cancer cells. To determine whether inhibition of the NF-kappa B pathway by parthenolide could sensitize pancreatic cancer cells to NSAID inhibition, BxPC-3, PANC-1, and MIA PaCa-2 cells were treated with parthenolide and the NSAID sulindac, either alone or in combination. Treatment with the combination of parthenolide and sulindac inhibited cell growth synergistically in MIA PaCa-2 and BxPC-3 cells and additively in PANC-1 cells. In addition, treatment with the parthenolide/sulindac combination lowered the threshold for apoptosis. Increased levels of I kappa B-alpha protein were detected, especially in MIA PaCa-2 cells, after treatment with parthenolide and sulindac compared with each agent alone. Similarly, decreased NF-kappa B DNA binding and transcriptional activities were detected in cells treated with the combination compared with the single agents, demonstrating cooperative targeting of the NF-kappa B pathway. These data provide preclinical support for a combined chemotherapeutic approach with NF-kappa B inhibitors and NSAIDs for the treatment of pancreatic adenocarcinoma.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Synergism; Humans; Models, Biological; NF-kappa B; Pancreatic Neoplasms; Phosphorylation; Protein Binding; Sesquiterpenes; Sulindac; Transcription, Genetic; Transfection

To study the effect of sulindac on colon cancer induction in mice.. The chemo-preventive action of 80 ppm sulindac fed during initiation and post-initiation and 100 ppm sulindac fed during progressive stages of induction of colon carcinogenesis in mice was investigated using 1,2-dimethylhydrazine (DMH). Using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) technique and PCNA immunohistochemical staining, we observed the apoptotic and proliferative cell density changes at different carcinogenic stages and the effect of sulindac on these two phenomena.. Dietary sulindac significantly inhibited the incidence of colonic neoplasmas in mice. Compared with the control group, feeding sulindac during initiation and post-initiation stages inhibited the incidence by 46.7-50.4%, and feeding sulindac during progressive stages inhibited the incidence by 41.1%. Animals that were fed sulindac showed less serious pathological changes than those that were fed the control diet (P<0.01, H = 33.35). There was no difference in the density of proliferating cells among those groups which were or were not fed sulindac. In the same period, feeding sulindac resulted in a higher density of apoptotic cells than feeding control diet.. Sulindac has an anti-carcinogenic function in mice. Its effect on preventing colon carcinogenesis is better than its effect on treating established tumors. By inducing apoptosis, sulindac inhibited the development of colon cancer and delayed canceration. Sulindac has no effect on proliferation. The anti-carcinogenic properties of sulindac are most effective in the moderate and severe stages of dysplasia and canceration.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma; Colonic Neoplasms; Diet; Male; Mice; Mice, Inbred Strains; Sulindac

Non-steroidal anti-inflammatory drugs (NSAIDs) are potent antitumoral agents but their side effects limit their clinical use. A novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), was found to be safer and more active than classical NSAIDs. This study explored the effect of the NO-donating sulindac derivative, NCX 1102, on three human urothelial epithelial carcinoma cell lines (T24, 647V, and 1207) and primary cultures of normal urothelial cells. Cytotoxicity, antiproliferative effect, cell cycle alterations, morphological changes, and apoptosis were investigated after treatment with NCX 1102 in comparison with the native molecule. After treatment, there was a cytotoxic effect (with IC(50) at 48 h of 23.1 micro M on 647V, 19.4 micro M on T24, and 14.5 micro M on 1207) and an antiproliferative effect on all three cell lines with NCX 1102 but not with sulindac. No effect was detected on normal urothelial cells. Flow cytometric analysis showed a differential NCX 1102-induced accumulation of cells in various phases of the cell cycle, depending on cell line and concentration. NCX 1102 induced an occurrence of multinucleated cells in all cell lines and mitotic arrest in 647V and 1207. NCX 1102-treated T24 and 647V cell lines showed a significant difference of apoptotic cell amount when compared to controls. Our results demonstrated a greater antiproliferative potency of NCX 1102 compared to its parent molecule sulindac, and suggested that this new NO-NSAID may have therapeutic impact in the management of bladder cancer.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Carcinoma; Cell Division; Cell Line, Tumor; Cell Nucleus; Dose-Response Relationship, Drug; Epithelium; Flow Cytometry; Humans; Inhibitory Concentration 50; Nitric Oxide; Sulindac; Time Factors; Urinary Bladder Neoplasms

Resistance to apoptosis may be responsible for a principal mechanism by which cancer cells overcome anticancer therapies. Among antiapoptotic signals, the transcription factor, NF-kappaB, plays a pivotal role in the resistance because it is frequently activated in many primary carcinoma cells. However, NF-kappaB is also activated by several anticancer therapies, including tumor necrosis factor-alpha (TNF-alpha). The NF-kappaB-mediated survival signals are supposed to evade these therapies. Recently, a nonsteroidal antiinflammatory drug, sulindac, and its metabolites have been shown to inhibit the NF-kappaB pathway and to enhance TNF-alpha-mediated apoptosis in lung carcinoma cell lines. In the current study, the authors investigated whether sulindac can augment TNF-alpha-mediated apoptosis in other human carcinoma cells and whether it can be applied for in vivo clinical usage.. Human gastric MKN45 and cervical HeLa carcinoma cells were treated with sulindac and/or TNF-alpha. Proapoptotic effects of these agents were evaluated by trypan blue exclusion assay, DNA fragmentation, and caspase-3 activity. The effect of sulindac on NF-kappaB activation was evaluated by luciferase reporter and gel-shift assays. The suppressive effects of these reagents on the subcutaneous tumor growth of MKN45 cells were evaluated by measuring tumor size in nude mice.. Sulindac inhibited TNF-alpha-mediated NF-kappaB activation and greatly sensitized MKN45 and HeLa cell lines to TNF-alpha. Moreover, in vivo tumor growth of MKN45 cells was inhibited most strongly by a combination of TNF-alpha with sulindac compared with TNF-alpha or sulindac alone.. The current study data strongly suggest that combination therapy of TNF-alpha with sulindac may sensitize tumor cells to TNF-alpha and augment its proapoptotic potential. Therefore, in combination with sulindac, TNF-alpha may become a potentially useful anticancer agent to suppress tumor growth in a wide range of carcinomas.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma; Drug Interactions; Drug Therapy, Combination; Female; HeLa Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Stomach Neoplasms; Sulindac; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

The present study was conducted to explore the potential role of proteasome pathway in NSAIDs-induced apoptosis. We employed sulindac as a NSAID, and chose the lactacystin for inhibition of proteasome activity. Assessment of apoptosis and proteasome activity assay were undertaken. We demonstrated that sulindac treatment resulted in a decrease of proteasome activity, and that the co-treatment of a proteasome inhibitor lactacystin potentiated the extent of sulindac-induced apoptosis in HT-29 cells by augmentation of the decrease in proteasome activity. Elucidation of the mechanism underlying the regression of colon cancers by combinations of sulindac and lactacystin seems to be an immediate challenge for the near future.

Topics: Acetylcysteine; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma; Cell Line, Tumor; Colonic Neoplasms; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Drug Synergism; HT29 Cells; Humans; Multienzyme Complexes; Proteasome Endopeptidase Complex; Reaction Time; Sulindac

Colorectal carcinomas are well known to highly express COX-2 and their growth is markedly inhibited by COX-2 inhibitors, but little is known about head and neck carcinomas. In this study, we investigated the effect of a selective COX-2 inhibitor, celecoxib, on growth and apoptosis induction of four human head and neck carcinoma cell lines, SCC25, KB, HSG and HSY, in comparison with frequently used COX inhibitor sulindac. Also, we examined whether celecoxib augments the sensitivity of these cell lines to anticancer drugs such as doxorubicin (DOX), vincristine (VCR), cisplatin (CDDP), bleomycin (BLM) and 5-fluorouracil (5-FU). The growth of all cultured cell lines particularly SCC25 and HSG was inhibited by celecoxib and sulindac in a dose-dependent manner. The IC50 of celecoxib was ten times lower than that of sulindac. SCC25 produced ample PGE2 whereas KB, HSG and HSY produced a small amount of PGE2. The PGE2 production and COX-2 expression were inhibited more efficiently by celecoxib than by sulindac. Exogenous addition of PGE2 resulted in an increased cell growth of SCC25 even under the celecoxib-treated condition, but not of HSG. These results suggested that PGE2 is involved in the growth of SCC25 but not of HSG. The ability of celecoxib to induce apoptosis is greater than that of sulindac. Treatment of SCC25 and HSG with non-cytotoxic 1 micro M or less cytotoxic 5 micro M of celecoxib enhanced the sensitivity of both cell lines to anticancer drugs, particularly in DOX, VCR and BLM two to ten times as demonstrated by lowering of IC50s. The enhanced rate was almost parallel to the degree of apoptosis induction. These findings indicated that a selective COX-2 inhibitor celecoxib inhibits cell proliferation, induces apoptosis and augments sensitivity to anticancer drugs in human head and neck carcinoma cells. Therefore, celecoxib would be useful as biological modulator in treatment of head and neck cancer.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Bleomycin; Blotting, Western; Carcinoma; Celecoxib; Cell Line, Tumor; Cell Survival; Cisplatin; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; DNA Fragmentation; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Fluorouracil; Head and Neck Neoplasms; Humans; Inhibitory Concentration 50; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Sulindac; Time Factors; Vincristine

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis and prevent or revert the growth of premalignant colonic polyps. They inhibit cyclooxygenase (COX) but recent data indicate that this is not the only or even the most important mechanism of inhibition in colorectal tumor cells. We have used colonic carcinoma and adenoma cell lines to study the effects of the NSAID sulindac sulfide, its COX-inactive metabolite, sulindac sulfone, and the isoenzyme-specific inhibitors SC58125, SC236 and SC58560 on tumor cell growth in relation to COX-2 expression and prostaglandin production. To establish the role of COX-2 in NSAID action, we constructed clones expressing different levels of COX-2 from SW480 cells. All five compounds inhibited DNA synthesis and/or induced apoptosis, each with a characteristic pattern. ID(50)s were very similar in all the cell lines and were independent of COX expression, except for the COX-1 inhibitor SC58560, which was least effective in HT29/HI1, the cell line expressing the highest level of COX-1 (ID(50) 70 microM; in other cells lines the ID(50) was 15 microM). For all other compounds ID(50) concentrations varied less than two-fold: 25-40, 40-90 and 150 microM for SC236, sulindac sulfide and sulindac sulfone, respectively. SC58125 was the weakest inhibitor, never causing >50% cell loss. All compounds modulated expression of Bcl-2 and Bak and activated caspase 3. Overexpression of COX-2 in SW480 cells protected them against induction of apoptosis by sulindac sulfide. The effect was restricted to clones producing high levels of prostaglandin E(2). In summary, our data indicate that both COX-dependent and COX-independent mechanisms are involved in NSAID-induced growth in colorectal tumor cells. The concentrations necessary to inhibit growth were higher than serum concentrations that can be obtained in vivo, indicating that the therapeutic effect of NSAIDs cannot be explained by a direct effect of NSAIDs on the epithelial cells alone. For therapeutic purposes, compounds using different targets could be used to minimize side effects while optimizing therapeutic effect.

Topics: Adenoma; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma; Cell Division; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Growth Inhibitors; HT29 Cells; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Substrate Specificity; Sulindac; Tumor Cells, Cultured

We tried to elucidate the effects of sulindac on human colorectal carcinoma.. Sulindac (300 mg/day) was administered for two weeks before operation to 33 patients with sporadic colorectal carcinoma (Sulindac Group). Resected specimens were used to detect apoptosis by terminal dUTP nick end labeling and transforming growth factor (TGF)-beta1 expression by immunohistochemistry. The results were compared with those from the historical Control Group. Twenty-nine available preoperative biopsies taken from carcinomas before sulindac prescription and 22 concurrent colorectal adenomas (9 and 13 in Sulindac and Control Groups, respectively) in the resected specimen were also examined regarding TGF-beta1 expression.. In the resected carcinomas and adenomas, more frequent apoptosis and higher TGF-beta1 scores were observed in the Sulindac Group than in the Control Group. Overexpression of TGF-beta1 and apoptosis occurred in the same region in adenomas but not in carcinomas. A positive correlation between TGF-beta1 scores and apoptotic frequency was found in adenomas (P = 0.01, rho = 0.91) but not in carcinomas (P = 0.89, rho = 0.03).. We conclude that sulindac induces apoptosis in human colorectal carcinomas as well as in adenomas. Also, one of the antineoplastic effects of sulindac might be mediated by upregulating TGF-beta1 expression, particularly in colorectal adenomas.

Topics: Adenoma; Aged; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Preoperative Care; Sulindac; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

As part of our screening program for cancer inhibitory agents effective specifically in the promotion stage of cancer development, we have evaluated the possible inhibitory effects of 36 non-steroidal anti-inflammatory drugs (NSAIDs) on the Epstein-Barr virus early antigen (EBV-EA) activation which was induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. All the drugs were observed to inhibit the EBV-EA activation at low doses with low toxicity. The two most active anti-tumor promoting agents were the arylacetic acid derivatives, etodolac and sulindac. We also report for the first time the activities of 14 new NSAIDs belonging to different classes as potential cancer chemopreventive agents. A structure-activity relationship study showed that among the salicylic acid derivative tested, the oxidation of the thiol group to dithiol derivatives results in the reduction of the activity. Introduction of amino group on the salicylic acid molecules also results in the reduction of activity in the EBV-EA assay. The results are of great interest in the development of NSAIDs as cancer chemopreventive agents, which halt cancer progression in multistage carcinogenesis, where successive activities are required to evolve into fully-fledged and metastatic cancer.

Topics: Acetates; Anti-Inflammatory Agents, Non-Steroidal; Antigens, Viral; Benzene; Carcinogens; Carcinoma; Cell Survival; Etodolac; Fluorescent Antibody Technique, Indirect; Humans; Nasopharyngeal Neoplasms; Neoplasms; Oxidation-Reduction; Salicylates; Structure-Activity Relationship; Sulindac; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Sulindac possesses an inhibitory effect on colorectal cancer development. Rat colon cancer cells, ACL-15, inoculated subcutaneously in F344 rats were used. Sulindac was administered at 8 mg/kg twice daily for 7 consecutive days. Sulindac group and control group were compared regarding tumor volume and body weight. At sacrifice, the tumors were collected and examined for tumor-infiltrating lymphocytes, apoptotic index, and microvessel density. The tumor volume in the sulindac group was significantly smaller than that in the control group. Body weight, microvessel density, and tumor-infiltrating lymphocyte score were not significantly different between the two groups. The apoptotic index was significantly higher in the sulindac group than in the control group. Sulindac inhibited tumor growth by inducing apoptosis. These findings may be helpful in designing new treatment strategies in colorectal cancer patients.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Blood Vessels; Carcinoma; Cell Division; Colonic Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Neoplasm Transplantation; Rats; Rats, Inbred F344; Sulindac

1. In this study we describe experiments to establish ex vivo the selectivity of non-steroidal anti-inflammatory drugs (NSAIDs) given in vivo. 2. Anaesthetised (Inactin, 120 mg kg(-1)) male Wistar rats (220-250 g) received an i.v. dose of one of the following compounds (dose mg kg(-1)): aspirin (20), diclofenac (3), L-745,337 (30), nimesulide (15), salicylate (20), sulindac (10). Blood samples were taken before and up to 6 h after dosing and the plasma obtained from it was tested for its ability to inhibit prostanoid formation in IL-1beta-treated A549 cells (COX-2 system) and human washed platelets (COX-1 system). For control the same compounds were also added directly to the assay systems. 3. All drugs, except sodium salicylate, inhibited COX-1 and COX-2 when added directly to the test systems. Plasma from aspirin-treated rats was without effect on either COX-1 or COX-2, consistent with the rapid in vivo metabolism to salicylate. Conversely, plasma from sulindac-treated rats inhibited COX-1 and COX-2 with potencies according with in vivo metabolism to sulindac sulphide. Diclofenac was COX-1/2 non-selective when tested in vitro, but a slightly preferential inhibitor of COX-2 when tested ex vivo. Nimesulide was confirmed as preferential inhibitor of COX-2 both in vitro and ex vivo. L-745,337 was a selective COX-2 inhibitor when tested in vitro or ex vivo. 4. In conclusion, our experiments show clearly (a) NSAIDs inactivation, (b) activation of prodrugs, and (c) NSAIDs selectivity. Our assay provides useful information about the selectivity of NSAIDs that could be extended by the analysis of plasma samples taken from humans similarly treated with test drugs.

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Blood Pressure; Carcinoma; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Humans; Indans; Isoenzymes; Male; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Salicylates; Substrate Specificity; Sulfonamides; Sulindac; Thromboxane B2; Tumor Cells, Cultured

Sulindac (cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl) benzylidene] indene-3-acetic acid), an inhibitor of prostaglandin synthesis, has been reported to cause regression of colon polyps in patients with familial polyposis coli and Gardner's syndrome. We examined the effect of sulindac on the growth of primary colon carcinomas in rats. Colon tumors were induced in 18 rats by repeated subcutaneous administration of dimethylhydrazine. The site and diameter of each tumor were measured via laparotomy and colonoscopy. Rats were randomized to receive either sulindac (10 mg/kg) twice daily or vehicle (0.5% methylcellulose). After 4 weeks of treatment, the site and size of tumors in the colon were again recorded. In eight rats receiving sulindac, no new tumors were identified, while in 10 control rats, 13 additional tumors were found after treatment. There was a significantly greater increase in size of the tumors in the control group (56.4 mm for 26 tumors) compared with the rats receiving sulindac (9.3 mm for 14 tumors). We report that sulindac inhibits the rate of development and the rate of growth of colon tumors in the rat.

Topics: Adenocarcinoma; Adenoma; Animals; Carcinoma; Colonic Neoplasms; Dimethylhydrazines; Male; Random Allocation; Rats; Rats, Inbred Strains; Remission Induction; Sulindac