sulindac and Carcinoma--Squamous-Cell

The study of green tea polyphenols as a cancer preventative is approaching a new era, with significant results accumulating rapidly. This paper briefly reviews four topics related to mechanisms of action of tea polyphenols: (I) identification of the genes commonly affected by EGCG, as demonstrated by Clontech's Atlas cDNA Expression Array; (II) the significance of heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1) as a new biomarker for early detection of lung cancer, and inhibition of its expression by EGCG; (III) the synergistic or additive effects of EGCG with the cancer preventive agents, sulindac and tamoxifen, on induction of apoptosis in PC-9 cells and on inhibition of intestinal tumor development in multiple intestinal neoplasia (Min) mice; (IV) the results of a 10 year prospective cohort study demonstrating the effectiveness of daily consumption of green tea in preventing cancer, and a prototype study for developing green tea beverage as cancer preventive.

Topics: Animals; Anticarcinogenic Agents; Biomarkers, Tumor; Carcinoma, Squamous Cell; Catechin; Chemoprevention; Cohort Studies; Drug Synergism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Heterogeneous-Nuclear Ribonucleoproteins; Humans; Intestinal Neoplasms; Japan; Lung Neoplasms; Male; Mice; Mice, Mutant Strains; Okadaic Acid; Oligonucleotide Array Sequence Analysis; Prospective Studies; Ribonucleoproteins; Sulindac; Tea; Tumor Cells, Cultured

The EGF receptor (EGFR) and COX2 pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic antitumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a nonselective COX inhibitor; versus placebo.. Patients with untreated, operable stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after seven to 14 days of treatment. The primary endpoint was change in Ki67 proliferation index. We hypothesized an ordering effect in Ki67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX2 signaling intermediates.. From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, P = 0.04). Wilcoxon pairwise contrasts confirmed greater Ki67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo, P = 0.043; erlotinib vs. placebo, P = 0.027). There was a significant trend in ordering of Ki67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, P = 0.0185). Low baseline pSrc correlated with greater Ki67 reduction (R(2) = 0.312, P = 0.024).. Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cohort Studies; Double-Blind Method; ErbB Receptors; Erlotinib Hydrochloride; Female; Follow-Up Studies; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Male; Middle Aged; Neoplasm Staging; Prognosis; Quinazolines; Sulindac; Tissue Array Analysis

Targeting the epidermal growth factor receptor (EGFR) using the tyrosine kinase inhibitor (TKI) erlotinib has demonstrated activity in aerodigestive tract malignancies. Co-targeting of the G-protein-coupled receptor cyclooxygenase (COX) with EGFR inhibitors has shown promise in preclinical models and early phase clinical studies.. We studied the modulation of serum proteins after neoadjuvant treatment with erlotinib with or without sulindac in head and neck cancer patients. In a prospective, randomized, double-blind clinical trial, paired serum samples were obtained before and after neoadjuvant treatment in three groups of patients (n = 23 total), who were randomized to receive 7-14 consecutive days of erlotinib alone, erlotinib plus sulindac, or placebo. Two separate multiplexed ELISA systems (SearchLight™ or Luminex™) were used to measure serum biomarkers. HGF and IL-6 levels were tested on both systems, and validated using single analyte ELISAs.. Several analytes were significantly altered (generally decreased) post-treatment, in patients who received erlotinib (with or without sulindac) as well as in the placebo groups. No single analyte was differentially altered across the three treatment groups using either multiplex platform. Single HGF ELISA suggested a nonspecific decrease in all patients.. These results demonstrate the importance of a placebo group when assessing changes in expression of serum biomarkers. While multiplex platforms can provide quantitative information on a large number of serum analytes, results should be cautiously compared across platforms due to their intrinsic features. Furthermore, the dynamic range of expression of a single analyte is constrained in multiplex versus standard ELISA.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Squamous Cell; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; ErbB Receptors; Erlotinib Hydrochloride; Female; Head and Neck Neoplasms; Hepatocyte Growth Factor; Humans; Interleukin-6; Male; Middle Aged; Neoadjuvant Therapy; Pilot Projects; Placebos; Prospective Studies; Protein Kinase Inhibitors; Quinazolines; Sulindac; Transforming Growth Factor alpha

This multicenter, phase II clinical trial was conducted to evaluate the activity of the combination of docetaxel and exisulind in advanced non-small cell lung cancer (NSCLC) patients who failed a prior platinum-containing regimen.. Patients with measurable disease and adequate organ function received exisulind (250 mg) given orally, twice daily, and docetaxel (36 mg/m) administered intravenously on days 1, 8, and 15 of a 4-week cycle for up to six cycles. In the absence of disease progression or intolerable side effects, patients continued taking 250 mg of exisulind orally, twice daily.. Thirty-three patients (median age 60 years; range 34-77; median performance status 1) were enrolled. There were no objective responses documented. Sixteen patients [48%, 95% confidence interval (CI): 31%-66%] had stable disease after 8 weeks of treatment. Median progression-free survival (PFS) was 2.1 months (95% CI: 1.5-3.2 months); median overall survival time was 8.0 months (range 0.2-25.9 months). Toxicity was moderate, with dose adjustment for adverse event/toxicity required for docetaxel or exisulind in 13 (39.3%) patients. Grade 3/4 lymphopenia, neutropenia, and anemia occurred in 48.5%, 12.1%, and 9.1% of patients, respectively. Grade 3 or greater toxicity was seen in 12.1%, 6.1%, and 3% of patients for nausea/vomiting, dyspnea, and abdominal pain, respectively.. Treatment with exisulind and weekly docetaxel was not active in NSCLC patients who failed a prior platinum-containing regimen. Further study of this combination does not seem warranted.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Combined Modality Therapy; Docetaxel; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Radiotherapy Dosage; Remission Induction; Sulindac; Survival Rate; Taxoids; Treatment Outcome

To evaluate the safety and efficacy of novel cobalt complex with sulindac (Co-SLD), the zebrafish and oral squamous cell carcinoma CAL27 were investigated in the present study. The developmental toxicity of Co-SLD ranging from 5 to 20 μM was determined by exposure to 3-144-h post-fertilization (hpf) zebrafish. Our data showed that Co-SLD did not cause to the appreciable toxicity at low concentration (5 and 10 μM). A remarkable toxicity was observed at high concentration (20 μM), including increased mortality and malformation, delayed hatchability, reduced heart rate as well as suppressed behaviour. With regard to the antitumor activity of Co-SLD, inhibited cell growth and migration capability were outstandingly observed in oral squamous cell carcinoma treated with 10 and 20 μM Co-SLD, which could be mainly attributed to the Co-SLD-elicited mitochondrial damage as marked by the depression of mitochondrial membrane potential, ROS accumulation and ATP depletion. Furthermore, administration of 10 μM Co-SLD was an optimal concentration not only to avoid the normal tissue toxicity, but also to enhance the killing of cancer cells via disrupting mitochondrial dysfunction. Taken together the above results demonstrated the desirable response of oral squamous cell carcinoma to Co-SLD.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cobalt; Coordination Complexes; Dose-Response Relationship, Drug; Humans; Locomotion; Mitochondria; Mouth Neoplasms; Sulindac; Zebrafish

The antineoplastic properties of the NSAID sulindac have long been studied. The purpose of this study was to explore sulindac's in vivo effects on oral squamous cell carcinoma (SCC) oncogenesis using the hamster cheek pouch oral carcinogenesis model (HOCM). Thirty Syrian golden hamsters were divided into three experimental and two control groups (n = 6 each). The animals' right buccal pouches were treated with carcinogen for 9 weeks in one experimental and one control group and for 14 weeks in all other three groups. The animals of two experimental groups received sulindac from the 1st week and those of the third experimental group from the 10th week. After the end of carcinogenesis, treated buccal pouches were removed and examined. In animals treated with carcinogen for 14 weeks, development of oral SCC and tumor volume were significantly lower in animals that received sulindac from the first week of the experiment. Oral SCC developing in animals that received sulindac were more frequently well differentiated compared with the control group. In animals treated with carcinogen for 9 weeks, the animals that received sulindac developed lower grade of epithelial dysplasia. Proliferation index Ki-67 and positivity for the antiapoptotic molecule survivin were lower in the animals that received sulindac. Treatment with sulindac appears to delays the progression of oral premalignant lesions to oral SCC in the HOCM, also resulting in smaller and better differentiated tumors. These in vivo antineoplastic effects may be related to sulindac's ability to decrease cell proliferation and to prevent survivin expression.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Carcinoma, Squamous Cell; Cricetinae; Disease Models, Animal; Immunohistochemistry; Male; Mesocricetus; Mouth Neoplasms; Sulindac

Phospho-sulindac (P-S, OXT-328), a novel sulindac derivative, has shown superior anticancer efficacy and safety compared to sulindac. In this study, we investigated the efficacy of topical P-S hydrogel in the treatment of non-melanoma skin cancer in preclinical models. P-S is a potent inhibitor of A431 epidermoid carcinoma in vitro and achieves this effect by inhibiting cell proliferation and inducing apoptosis. The anticancer efficacy of topical and oral P-S was further evaluated in mice bearing A431 intradermal xenografts. Compared to the controls, topical P-S hydrogel inhibited the A431 xenografts by 70.5% (p<0.01), while oral P-S inhibited it by 43.4% (p<0.05), being significantly less effective than topical P-S (p=0.017). Topical P-S hydrogel generated significant levels (>500 nmol/g tumor tissue) of intact P-S in the tumors, accounting for 92.5% of the total metabolites in the A431 xenografts. This local delivery of high levels of intact P-S to the A431 xenografts is an important contributor to the potent activity of topical P-S and no local or systemic side effects were noted in the treatment group. Thus, topical P-S is a promising treatment modality against non-melanoma skin cancer and merits further evaluation.

Topics: Administration, Topical; Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Humans; Mice; Organophosphorus Compounds; Skin Neoplasms; Sulindac; Xenograft Model Antitumor Assays

The most common neoplasm arising in the upper gastrointestinal tract is head and neck squamous cell carcinoma (HNSCC). This is an aggressive epithelial malignancy. Many growth factors and cytokines have been discovered that are responsible for the growth and formation of tumours. Among these factors, beta-catenin is considered to be the most important for reducing cell-cell adhesions in malignant tissue. The degradation of beta-catenin triggers apoptosis by different routes. Sulindac sulfone has been shown to induce apoptosis in several different tumours. In the present study, we surveyed the concentration of beta-catenin in an HNSCC line after incubation with different concentrations of sulindac sulfone.. Immunohistochemical and Western blot analyses were performed after treatment of the UMSCC 11A cell line with different concentrations of sulindac sulfone (100, 200, 400, 600 and 800 microMol) for 48 hours.. At 100 microMol of sulindac sulfone, a decrease in beta-catenin concentration of 5% was observed; increasing concentrations of sulindac sulfone resulted in >70% reduction in secreted beta-catenin. Thus in conclusion, incubation with sulindac sulfone seemed to stop proliferation. With respect to the controls, there was no greater reduction in total protein.. In this study, sulindac sulfone reduced levels of secreted beta-catenin in the HNSCC cell line UM-SCC 11A after 48 hours of incubation. It is presumed that reduction of cell-cell adhesion, which is predominately affected by beta-catenin, is an essential step in the progression from localized malignancy to stromal and vascular invasion and ultimately metastatic disease. The reduction in the level of mural expression of beta-catenin has been associated with loss of differentiation in laryngeal carcinomas. Thus, prevention of intracellular beta-catenin accumulation is regarded as an attractive target for chemopreventive agents.

Topics: Antineoplastic Agents; beta Catenin; Blotting, Western; Carcinoma, Squamous Cell; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Sulindac; Tumor Cells, Cultured

Actinic keratoses (AKs) are a precancerous condition of the skin that have the potential to become squamous cell cancer (SCC). Sulindac is a Food and Drug Administration (FDA)-approved nonsteroidal anti-inflammatory drug (NSAID) that has been shown to have clinically significant anticancer effects. Malignant cells may have a different response to oxidative stress than normal cells.. To establish a role of increased reactive oxygen species (ROS) in the mechanism of cancer killing by sulindac in the presence of an oxidizing agent. To assess the tolerability and efficacy of the combination of gels containing sulindac and hydrogen peroxide in the treatment of patients with AKs.. Cell culture studies were performed using a skin SCC cell line and normal human epidermal keratinocytes. After treatment with sulindac and an oxidizing agent, cell viability, and intracellular ROS levels were measured. An open-label clinical trial was performed using sulindac and hydrogen peroxide gels daily for 3 weeks on AKs involving the upper extremities.. In SCC cells, a combination of sulindac and an oxidizing agent lead to 400 to 500% increases in intracellular ROS, which resulted in significant cell death. In sharp contrast, normal keratinocytes did not show increases in ROS levels and were not killed. A clinical trial using the combination of sulindac and hydrogen peroxide therapy in 5 patients with AKs revealed that 60% of the treated AKs responded and 50% showed no residual AK on histopathology specimens after skin biopsy.. The small number of patients and the lack of a placebo group.. Increased levels of ROS appear to be important in the selective killing of cancer cells in the presence of sulindac and oxidizing agents. Further studies are necessary to define the role of the combination of sulindac and oxidizing agent therapy in patients with AKs and skin cancer.

Topics: Administration, Topical; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Drug Therapy, Combination; Gels; Humans; Hydrogen Peroxide; Keratosis, Actinic; Oxidants; Oxidative Stress; Reactive Oxygen Species; Skin Neoplasms; Sulindac

Sulindac sulfide and sulindac sulfone have demonstrated anti-neoplastic and chemo-preventive activity against various human tumors, but few studies have examined the relative effectiveness of these drugs against squamous cell carcinoma of the head and neck (SCCHN). These compounds are metabolites of the nonsteroidal anti-inflammatory drug sulindac and differ in their ability to inhibit cyclooxygenase-2 (COX-2) enzyme function. Sulindac sulfide (the sulindac metabolite with COX-2 inhibitory function) demonstrated strong cell growth inhibition as measured by MTT and growth assays in UM-SCC-1 and SCC-25 cells, while sulindac sulfone had only moderate effect. Growth inhibition by sulindac sulfide was associated with a significant increase in percent G cells and activation of caspase-3. Sulindac sulfide induced expression of p21wafl/cipl in a dose-dependent fashion, decreased cyclin D1 protein levels, and increased Rb hypophosphorylation. p21waf1/cip1 protein levels increased without a significant increase in wild-type p53, suggesting that sulindac sulfide induces a p53-independent pathway regulating p2lwafl/ciP1 protein levels in SCCHN. Sulindac sulfide also induced dose-dependent expression of PPAR-gamma. In contrast, sulindac sulfone did not significantly alter apoptosis, cell cycle distribution or G1 checkpoint protein expression at doses below 200 microM. These results demonstrate the differential activity of sulindac metabolites and support the hypothesis that sulindac sulfide induced perturbations in SCCHN cellular proliferation could be regulated both by p21waf1/cip1-dependent cytostatic and caspase-dependent cytotoxic pathways.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Cycle; Cell Cycle Proteins; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Head and Neck Neoplasms; Humans; PPAR gamma; Sulindac; Tumor Suppressor Protein p53; Up-Regulation

Sulindac has antineoplastic effects on various cancer cell lines; consequently, we assessed sulindac's effects on laryngeal squamous cell carcinoma (SCC) cells in vitro and in vivo. In vitro, SCC (HEP-2) cells treated with various cyclooxygenase inhibitors or transfected with constitutively active signal transducer and activator of transcription 3 (Stat3) or survivin vectors were analyzed using Western blot analysis, annexin V assay, and cell proliferation assay. In parallel, nude mice injected subcutaneously with HEP-2 cells were either treated intraperitoneally with sulindac or left untreated, and analyzed for tumor weight, survivin expression, and tyrosine-phosphorylated Stat3 expression. In vitro studies confirmed the selective antiproliferative and proapoptotic effects of sulindac, which also downregulated Stat3 and survivin protein expression. Stat3 or survivin forced expression partially rescued the antiproliferative effects of sulindac. In vivo studies showed significant repression of HEP-2 xenograft growth in sulindactreated mice versus controls, with near-complete resolution at 10 days. Additionally, tumor specimens treated with sulindac showed downregulation of phosphorylated tyrosine-705 Stat3 and survivin expression. Taken together, our data suggest, for the first time, a specific inhibitory effect of sulindac on tumor growth and survivin expression in laryngeal cancer, both in vitro and in vivo, in a Stat3-dependent manner, suggesting a novel therapeutic approach to head and neck cancer.

Topics: Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase Inhibitors; Female; Head and Neck Neoplasms; Humans; Inhibitor of Apoptosis Proteins; Mice; Microtubule-Associated Proteins; Neoplasm Proteins; Neoplasm Transplantation; Phosphorylation; STAT3 Transcription Factor; Sulindac; Survivin; Transplantation, Heterologous

Sulindac exerts its antitumorigenic effects in oral squamous cell carcinoma (SCC) cells by modulating survivin in a Stat3-dependent manner. Immunohistochemistry was used to detect the protein levels of phosphorylated-tyrosine Stat3 (p-tyr Stat3) and survivin in SCC tissues. Western blot, reverse transcriptase polymerase chain reaction, Annexin-V and cell proliferation assays were used to determine p-tyr Stat3 and survivin protein and mRNA expression, and cell viability following treatment with cyclooxygenase (COX) inhibitors, Stat3 siRNA, or the forced expression of Stat3 or survivin. Immunohistochemical analysis revealed an overexpression of p-tyr Stat3 in T1 SCCs. The importance of constitutive Stat3 activation in tumourigenesis was confirmed by siRNA inhibition of Stat3, resulting in cell growth inhibition and apoptosis, via a downregulation of survivin mRNA and protein expression. The forced expression of survivin partially reversed these effects of Stat3 inhibition. Sulindac, but not other COX inhibitors, downregulated Stat3, which correlated to an inhibition of cell proliferation, survival and survivin expression. Transfection of constitutively active Stat3 restored survivin expression and partially rescued SCC cells from sulindac-induced antitumorigenic effects. These data indicate that survivin is a downstream target and effector of oncogenic Stat3 signalling in SCC, which is targeted by sulindac in a COX-2-independent manner.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Celecoxib; Cell Division; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 2 Inhibitors; Cysteine Proteinase Inhibitors; Down-Regulation; Enzyme Inhibitors; Humans; Immunohistochemistry; Indomethacin; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Pyrazoles; Signal Transduction; STAT3 Transcription Factor; Sulfonamides; Sulindac; Survivin; Tongue Neoplasms; Tumor Cells, Cultured

Approximately 310,000 new cases of oral and pharynx cancer account for a major cause of neoplasm related morbidity and mortality world-wide. Unfortunately, the survival rate has not improved significantly in the last decade. The vast majority of head and neck cancer is squamous cell carcinoma. The major adhesion-proteins involved in the development and maintenance of all solid tissue are the Cadherins. Cadherins are the transmembrane components of the adherent junction with interaction with plakoglobin and beta-catenin. Downregulation of Cadherins and catenins is frequently observed in many types of human cancer. Sulindac sulfone is one of the new therapeutic apoptotic agents that show promise in the treatment of cancer. In this study, we incubated sulindac sulfone with a head and neck cancer cell line and investigated the outcome of E-Cadherin. Immunohistochemical and Western blot analyses were then performed, with different concentrations of sulindac sulfone (100, 200, 400, 600, and 800 microMol) for 48 h. At 400 microMol of sulindac sulfone a decrease of 21% was observed; at 600 microMol, 44% decrease of beta-catenin concentration was seen, and incubation with 800 microMol resulted in 73% reduction of secreted beta-catenin. Incubation with sulindac sulfone seemed to stop proliferation; however, with respect to the controls, there was no increased reduction of the total protein. Sulindac sulfone resulted in an increase of E-Cadherin content in the head and neck squamous cell cancer cell line after 48 h of incubation; however, the reactivity was restricted to the adherent junctions. At increasing concentrations of sulindac sulfone, intercellular E-Cadherin immunostaining intensifyied. ELISA also depicted significant rising levels of E-Cadherin. Sulindac sulfone contributes to the inactivation of cGMP phospho-diesterase. Thus, the accumulation of cellular cGMP and protein kinase G is induced. The following degradation of the phosphorylated beta-catenin and the dissociation from the Cadherin-catenin complex releases E-Cadherin. This may also contribute to growth inhibition and co-ordinate with apoptosis induction. It is not really clear as to, which pathway results in the elevation of the E-Cadherin proteins. However, in epithelial cancer cells, the Cadherin-catenin complex serves as a target for the chemopreventive agent, sulindac sulfone.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antineoplastic Agents; Apoptosis; beta Catenin; Cadherins; Carcinoma, Squamous Cell; Cell Adhesion; Cyclic GMP; Head and Neck Neoplasms; Humans; Immunohistochemistry; Protein Kinase C; Sulindac; Tumor Cells, Cultured; Up-Regulation

These results demonstrate that sulindac sulfide can induce cell death in maxillary cancer cells, and that sulindac sulfide-induced apoptosis is related to the extracellular signal-regulated kinase/p38 MAPK-caspase 3 signaling pathway.. Head and neck cancer is the sixth commonest cancer in the human body. Squamous cell carcinoma accounts for most sinonasal cancers. However, little is known regarding the biochemical mechanism(s) of cell death in sinonasal cancers. Recently, human epidemiological and clinical intervention studies have indicated that sulindac, a non-steroidal anti-inflammatory drug, exhibits chemopreventive activity in colorectal cancer. In this study, we aimed to investigate whether sulindac sulfide can induce apoptosis in sinonasal cancer cells and what type of molecular mechanisms induces the death of sinonasal cancer cells.. Sinonasal cancer cells (Asan Medical Center Head and Neck Cancer 5) were treated with various concentrations of sulindac sulfide. The degree of cell death was determined by means of a fluorescence-activated cell scan and the signal transduction pathway for cell death was examined.. Human nasal cavity cancer cells treated with sulindac sulfide underwent cell death, and the induction of apoptosis occurred in a dose-dependent manner. Moreover, sulindac sulfide-induced apoptosis was abolished by treatment with the caspase inhibitor Z-VAD-fmk and the mitogen-activated protein kinase (MAPK) inhibitors PD98059 and SB203580.

Topics: Amino Acid Chloromethyl Ketones; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma, Squamous Cell; Caspase Inhibitors; Flavonoids; Fluorescence; Humans; Imidazoles; Mitogen-Activated Protein Kinases; Paranasal Sinus Neoplasms; Pyridines; Signal Transduction; Sulindac

The nonsteroidal anti-inflammatory drug sulindac exerts a significant antineoplastic effect on several types of human cancers including oral squamous cell carcinoma (SCCa). Because constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been linked to carcinogenesis of various tumors including head and neck SCCa, we studied whether sulindac treatment affects the Stat3 signaling pathway in oral SCCa cells. Western blot experiments showed that short-term treatment of cells with sulindac resulted in a large reduction of phosphorylated Stat3, without significantly affecting Stat3 protein levels. In contrast, 3 days of sulindac treatment eliminated both phosphorylated and unphosphorylated Stat3 protein levels. Also, sulindac treatment exerted a significant time-dependent cell growth-inhibitory effect on oral SCCa cells under the same conditions shown to induce Stat3 down-modulation. The sulfone metabolite of sulindac, which lacks cyclooxygenase-inhibitory activity, did not affect either Stat3 expression or Stat3 phosphorylation. Antisense oligonucleotide treatment against peroxisome proliferator-activated receptor gamma did not attenuate the ability of sulindac to down-regulate Stat3. Our results suggest that down-modulation of Stat3 can be induced by sulindac treatment, thus possibly contributing to the antineoplastic effect of this drug.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Division; DNA-Binding Proteins; Down-Regulation; Humans; Mouth Neoplasms; Oligonucleotides, Antisense; Phosphorylation; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Sulindac; Trans-Activators; Transcription Factors; Tumor Cells, Cultured

There is strong evidence that nonsteroidal antiinflammatory drug (NSAID) sulindac may exert a significant antineoplastic effect. The purpose of our study was to explore the effects of sulindac on human oral squamous cell carcinoma (SCCa) cells and to elucidate the underlying molecular mechanisms. The changes that sulindac treatment induced on growth, apoptosis and cell cycle distribution of human oral SCCa cell lines were assessed by cell growth and flow cytometry experiments. Utilizing quantitative RT-PCR and immunocytochemistry, we determined the effect of sulindac treatment on mRNA and protein expression of different sulindac's targets. Also, PPARgamma expression was selectively targeted by antisense oligonucleotide treatment. Both sulfide and sulfone metabolites of sulindac, which differ in the ability to cause COX-2 inhibition, induced a significant dose- and time-dependent cell growth reduction accompanied by increase in apoptosis without concomitant cell cycle arrest. Sulindac treatment also caused upregulation of the protein and mRNA expression levels of COX-2 and PPARs. Treatment with antisense PPARgamma oligonucleotides abolished sulindac's growth inhibitory effect. Our results are consistent with a significant growth inhibitory effect of NSAID sulindac on human oral SCCa cells, which is mediated, at least partially, through induction of apoptosis. We suggest that upregulation of PPARgamma expression and activation may be, at least partially, responsible for sulindac's antiproliferative effect.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle; Cell Division; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; DNA Primers; Flow Cytometry; Humans; Immunoenzyme Techniques; Isoenzymes; Membrane Proteins; Mouth Neoplasms; Oligonucleotides, Antisense; Prostaglandin-Endoperoxide Synthases; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulindac; Transcription Factors; Tumor Cells, Cultured; Up-Regulation

In previous studies, we have found that expression of 15-lipoxygenase-1 (15-LOX-1) and its main product, 13-S-hydroxyoctadecadienoic acid, are decreased in human colorectal cancers and that nonsteroidal anti-inflammatory drugs (NSAIDs) can therapeutically induce 15-LOX-1 expression to trigger apoptosis in human colorectal cancer cells. NSAIDs similarly induce apoptosis in esophageal cancer cells, although the mechanisms of these effects remain to be defined. In the present study, we tested whether 15-LOX-1 is down-regulated in human esophageal cancers using paired normal and tumor human surgical samples and whether NSAIDs can up-regulate 15-LOX-1 to restore apoptosis in esophageal cancer cells. We found that: (a) 15-LOX-1 was down-regulated in human esophageal carcinomas; (b) NSAIDs induced 15-LOX-1 expression during apoptosis in esophageal cancer cells; and (c) 15-LOX-1 inhibition suppressed NSAID-induced apoptosis, which was restored by 13-S-hydroxyoctadecadienoic acid but not by its parent compound, linoleic acid. These findings demonstrate that 15-LOX-1 is down-regulated in human esophageal carcinomas and that NSAIDs induce apoptosis in esophageal cancer cells via up-regulation of 15-LOX-1. They also support the concept that the loss of the proapoptotic role of 15-LOX-1 in epithelial cancers is not limited to human colorectal cancers.

Topics: Adenocarcinoma; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Arachidonate 15-Lipoxygenase; Carcinoma, Squamous Cell; Enzyme Induction; Esophageal Neoplasms; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Linoleic Acids; Nitrobenzenes; Sulfonamides; Sulindac; Up-Regulation

Cyclooxygenase-II (Cox-II) overexpression is involved in the progression of various subtypes of cancer. We investigated the significance of Cox-II in the progression of malignant melanomas (MMs). Using immunohistology we determined that Cox-II is not expressed in 70 benign and malignant melanocytic tumours. Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) were also analysed as controls: the BCCs were consistently Cox-II negative (n = 11), whereas the SCCs showed moderate to strong Cox-II expression in 53% (n = 17). Reverse transcription-polymerase chain reaction and Western blotting of MM cell lines and MM tissues confirmed the lack of Cox-II expression in MM. However, in vitro the Cox-inhibiting non-steroidal anti-inflammatory drug (NSAID) sulindac sulphide (SIS) was significantly more effective in inducing apoptosis than sulindac sulphone (SOS), a derivative with a negligible effect on Cox (P < 0.01). The SIS doses needed for the induction of apoptosis were not significantly different in MM cell lines versus a Cox-II-positive colon carcinoma cell line (HT29). Furthermore, add-back experiments with high doses of the prostaglandins PGE2 and PGF2beta, major Cox-II products, did not abrogate this effect. We conclude that Cox-II expression is not involved in the progression of MM, and NSAID-induced apoptosis in MM cell lines seems to follow pathways independent of Cox-II. Nevertheless, Cox-II inhibitors are still candidates for therapy, though they act via an unknown mechanism.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Blotting, Western; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cell Differentiation; Child; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Progression; DNA Primers; Enzyme-Linked Immunosorbent Assay; Humans; Immunoenzyme Techniques; Isoenzymes; Melanoma; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; RNA; Skin Neoplasms; Sulindac; Tumor Cells, Cultured

The nonsteroidal antiinflammatory drug sulindac (sulfoxide) is known to cause regression and prevent recurrence of adenomas in patients with familial adenomatous polyposis. The mechanism of action does not appear to require inhibition of prostaglandin synthesis since the sulfone metabolite of sulindac (FGN-1) retains the antineoplastic properties of sulindac but lacks inhibitory effects on cyclooxygenase, types 1 and 2. FGN-1 has been shown to induce apoptosis in a variety of tumor cell lines, and selective apoptosis of neoplastic cells has been proposed to account for its antineoplastic properties. Since angiogenesis is necessary for tumor progression and may be related to apoptosis, it is possible that inhibition of angiogenesis may also contribute to the antineoplastic properties of sulindac or FGN-1. In order to test this possibility, cells derived from several different types of human lung tumors were grafted intradermally in Balb/c mice. Sulindac sulfoxide and its sulfide and sulfone metabolites were administered for 3 days orally, in a daily dose of 0.025-0.5 mg, and angiogenesis was measured after 72 h using a previously described method. The results showed that sulindac sulfoxide and sulfone statistically inhibited angiogenesis.

Topics: Adenocarcinoma; Adult; Aged; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Middle Aged; Neoplasm Transplantation; Neovascularization, Pathologic; Sulindac