sc-236 and Colonic-Neoplasms

The interactions of cigarette smoking with COX-2 on colitis and colitis-associated adenoma formation were studied. Mice were induced with colitis and exposed to cigarette smoke (CS) and/or SC236 (a COX-2 inhibitor). Results indicated that CS did not alter acute colonic inflammation. Addition of SC236 abolished the induction of proliferation and oxidative damage by colitis. Chronic SC236 treatment abolished the promoting effect of CS on colonic adenoma formation, via suppression of COX-2- and VEGF-mediated proliferation and angiogenesis, and reversed bcl-2-mediated inhibition of apoptosis by CS. To conclude, COX-2 inhibitor could be an implication on cancer prevention in smokers with chronic colitis.

Topics: Adenoma; Animals; Apoptosis; Cell Proliferation; Colitis, Ulcerative; Colonic Neoplasms; Cyclooxygenase 2; Dextran Sulfate; Male; Mice; Mice, Inbred BALB C; Pyrazoles; Smoking; Sulfonamides

Telomerase activation, which is observed in most human cancers, plays an important role in carcinogenesis. Human telomerase reverse transcriptase (hTERT) is a subunit of telomerase that is essential for telomerase activity. The aim of the study was to investigate whether nonsteroidal antiinflammatory drugs (NSAIDs) inhibit telomerase activity and hTERT.. Four colon carcinoma cell lines, HT-29, COLO205, CRL-2134, and SW1116, were used in the experiments. Polymerase chain reaction-based telomeric repeat amplification (TRAP) enzyme-linked immunosorbent assay (ELISA) was used to measure telomerase activity in the cells after treatment with aspirin, indomethacin, or SC-236 (a specific cyclooxygenase-2 [COX-2] inhibitor). Expression of hTERT mRNA and protein was detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. The dual luciferase reporter assay was performed to identify the potential cis-response elements to NSAIDs in the promoter region of hTERT.. Aspirin, indomethacin, and SC-236 inhibited telomerase activity in HT-29, COLO205, and CRL-2134 cell lines, but not in the SW1116 cell line. NSAIDs inhibited hTERT mRNA and protein expression through suppression of hTERT transcriptional activity. The hTERT promoter fragment -145 to -330 basepairs (bp) upstream of the ATG starting site was sufficient to respond to the NSAID-induced inhibitory effect and the inhibition was COX-2-independent.. NSAIDs inhibit telomerase activity at hTERT transcriptional, mRNA, and protein levels in colon carcinoma cells. The hTERT promoter fragment -145 to -330 bp may be the cis-response element to NSAIDs.

Topics: Adenocarcinoma; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blotting, Western; Colonic Neoplasms; Cyclooxygenase 2; Cyclooxygenase Inhibitors; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Humans; Indomethacin; Luciferases; Promoter Regions, Genetic; Pyrazoles; Response Elements; RNA, Messenger; RNA, Neoplasm; Sulfonamides; Telomerase; Transcription, Genetic; Tumor Cells, Cultured

Cigarette smoking, cyclooxygenase-2 (COX-2) and macrophages are independently associated with colorectal cancer. In the present study, cigarette smoke ethanol extract was applied to colon cancer cells (SW1116) or indirectly via activated macrophages (THP-1 cells) to attest their effects on cancer cell proliferation and tumor growth both in vitro and in vivo. Ethanol extract induced COX-2 expression in SW1116 and THP-1 cells. Combination of THP-1 pre-incubated medium and ethanol extract further potentiated COX-2 expression and proliferation of SW1116 cells. Tumor growth in nude mice was positively associated with the medium and/or ethanol extract treatments, together with the up-regulation of cell proliferation and angiogenesis, and down-regulation of apoptosis. Application of a COX-2 inhibitor (SC236) reduced tumor growth as well as cell proliferation and angiogenesis. These actions are partially depended on the decrease of COX-2 expression. Taken together, inhibition of COX-2 activity may have significant implication to prevent colon cancer in smokers.

Topics: Animals; Apoptosis; Cell Line; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Complex Mixtures; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Ethanol; Humans; Macrophages; Membrane Proteins; Mice; Mice, Nude; Neovascularization, Pathologic; Nicotiana; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Smoke; Sulfonamides; Thymidine; Time Factors; Tritium; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

High consumption of dietary fat promotes colon carcinogenesis. While this effect is well known the underlying mechanism is not understood. Fatty acid hydroperoxides (LOOH) arise from unsaturated fatty acids in the presence of oxygen and elevated temperature during food processing. An approach was made starting from the assumption that LOOH are present in dietary fats as a result of boiling. LOOH undergoes homolytic cleavage in the presence of iron. We studied their effects on gene expression in colorectal tumour cells using linoleic acid hydroperoxide (LOOH) as model compound. Addition to the medium of LT97 adenoma and SW480 carcinoma cells enhanced the production of hydrogen peroxide. Both cell lines were observed to increase VEGF and COX-II expression based on mRNA. Expression of VEGF was inhibited by caroverine and ubiquinon.

Topics: Adenoma; Carcinoma; Colonic Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dietary Fats; Gene Expression Regulation, Neoplastic; Humans; Linoleic Acids; Lipid Peroxides; Organic Chemicals; Pyrazoles; Quinoxalines; Sulfonamides; Tumor Cells, Cultured; Ubiquinone; Vascular Endothelial Growth Factor A

Selective cyclooxygenase-2 (COX-2) inhibitors are promising anti-inflammatory drugs with potential antitumor activities. The nuclear factor-kappa B (NF-kappaB) family of proteins is important transcriptional regulators of genes involved in immunity, inflammation, and carcinogenesis. In the present study, we investigated whether and by which molecular mechanism the selective COX-2 inhibitors inhibit NF-kappaB activation in gastric cancer. The effects of SC236 and its derivative, but devoid of COX-2 enzyme inhibition activity on NF-kappaB signaling, were evaluated using electromobility shift, transfection, and reporter gene assay. The translocation of RelA/p65 was investigated using Western blotting and immunocytochemistry. We showed that SC236 suppressed NF-kappaB-mediated gene transcription and binding activity in gastric cancer. This effect occurred through a mechanism independent of cyclooxygenase activity and prostaglandin synthesis. Furthermore, unlike aspirin, SC236 affected neither the phosphorylation, degradation, nor expression of IkappaB-alpha, suggesting that the effects of SC236 are independent of IKK activity and IkappaB-alpha gene transcription. Instead, SC236 worked directly through suppressing nuclear translocation of RelA/p65. It is possible that SC236 directly targets proteins that facilitate the nuclear translocation of NF-kappaB. Our study suggests an important molecular mechanism by which COX-2 inhibitors reduce inflammation and suppress carcinogenesis in gastrointestinal tract.

Topics: Active Transport, Cell Nucleus; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Colonic Neoplasms; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; DNA, Neoplasm; Enzyme Activation; Humans; I-kappa B Kinase; I-kappa B Proteins; Isoenzymes; Membrane Proteins; Neoplasm Proteins; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Prostaglandin-Endoperoxide Synthases; Protein Binding; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Pyrazoles; Stomach Neoplasms; Sulfonamides; Tetradecanoylphorbol Acetate; Transcription Factor RelA; Transcription, Genetic; Transfection; Tumor Necrosis Factor-alpha

The role of Cox-2 in NSAID-induced apoptosis is debated. We studied the role of Cox-2 inhibition in apoptosis induced by a selective Cox-2 inhibitor, SC236 (a structural analogue of celecoxib) in two colon cancer cell lines, HT29 (expressing Cox-2 protein) and HCT116 (not expressing Cox-2 protein). Apoptosis was quantified by flow cytometry. SC236 0-75 microM decreased cell numbers and induced apoptosis to identical levels in HT29 and HCT116 cells. However, SC236, concentrations >75 microM reduced Cox-2 protein expression in HT29 cells and induced greater levels of apoptosis in HT29 than in HCT116 cells. In contrast, sulindac sulfide (SSD) (which inhibits Cox-1 and Cox-2) 0-200 microM or sulindac sulfone (SSN) 0-500 microM (without significant activity against Cox-1 or Cox-2) caused identical decreases in cell number and increases in apoptosis in HT29 and HCT116 cells. Neither SSD nor SSN altered the expression of Cox-2 in HT29 cells. To determine that the higher levels of apoptosis in HT29 cells with SC236 >75 microM were related to decreased Cox-2 protein levels, we decreased Cox-2 protein expression in HT29 cells with curcumin (diferuloylmethane) and studied its effect on SC236-induced apoptosis. Curcumin augmented apoptosis induced by SC236 in HT29 cells but not in Cox-2 lacking HCT116 cells. In conclusion, selective Cox-2 inhibitors can induce apoptosis independent of Cox-2 expression. However they may selectively target cells that express Cox-2 by decreasing their Cox-2 protein expression.

Topics: Antineoplastic Agents; Apoptosis; Colonic Neoplasms; Curcumin; Cyclooxygenase 2; Isoenzymes; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Sulindac