sulindac-sulfide and Carcinoma--Squamous-Cell

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

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

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

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