COX-2 inhibitor, NS398, enhances Fas-mediated apoptosis via modulation of the PTEN-Akt pathway in human gastric carcinoma cell lines.
ABSTRACT A variety of human cancer cells are resistant to Fas ligand and anti-Fas antibody induced apoptosis. Previously, we reported that human gastric carcinoma cell lines were resistant to the anti-Fas antibody, CH-11, without interferon-gamma pretreatment in vitro. Cyclooxygenase (COX)-2 is known to be expressed in many human malignancies, and is correlated with tumor progression and resistance to apoptosis. This study examined whether NS398, a COX-2 inhibitor, inhibited cell proliferation and increased Fas-mediated apoptosis in human gastric carcinoma cell lines. Treatment of NS398 inhibited cell proliferation in MKN-45, which expressed the highest level of COX-2 among seven human gastric carcinoma cell lines, in a dose- and time-dependent manner, in contrast to less prominent effects in KATO-III, which expresses no COX-2. Although the treatment of CH-11 induced apoptosis in both cells, the simultaneous treatment of NS398 and CH-11 remarkably induced apoptosis, as confirmed by Hoechst 33258 staining and the terminal deoxynucleotidyl transferase- mediated dUTP-digoxigenin nick-end labeling (TUNEL) method in MKN-45. Flow cytometric analysis also revealed the increased pre-G1 fraction by the simultaneous treatment. The treatment of NS398 induced upregulation of Bad and PTEN, and downregulation of phosphorylated Akt (Thr308). These findings suggest that COX-2 might inhibit Fas-mediated apoptosis in human gastric carcinoma cell lines, especially MKN-45, by modulating PTEN and Akt.
SourceAvailable from: Shinichi Kawai[Show abstract] [Hide abstract]
ABSTRACT: Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the articular synovial tissues. Although the etiology of RA has not yet been elucidated, physical and biochemical inhibition of synovial hyperplasia, which is the origin of articular destruction, may be an effective treatment for RA. Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used for the treatment of RA. The mechanism of action of NSAIDs generally involves the inhibition of cyclooxygenase (COX) at sites of inflammation. Thus, NSAIDs were not generally considered to have a so-called anti-rheumatic effect, including inhibition of progressive joint destruction and induction of remission. However, certain conventional NSAIDs and celecoxib, a selective COX-2 inhibitor, have been reported to inhibit synovial hyperplasia by inducing the apoptosis of human synovial fibroblasts. Therefore, it has been suggested that such NSAIDs may not only have an anti-inflammatory effect but also an anti-rheumatic effect. In this review, we summarize findings about the pro-apoptotic effect, in other words, anti-proliferative effect of NSAIDs on synovial fibroblasts from patients with RA.Modern Rheumatology 12/2008; 18(6):542-51. DOI:10.1007/s10165-008-0102-8 · 2.21 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Many pathological conditions including most cancers show an exacerbated activation of the inflammatory pathways and their sustained maintenance. In cervical carcinogenesis, the hyperactivation of the inflammatory pathways plays an important role in tumorigenesis, progression of the disease from low-grade lesions to invasive cervical cancer as well as in the initiation of other infections such as HIV. Cyclooxygenase-2 (COX-2) is the inducible isoform of cyclooxygenases regulated by growth factors and cytokines, hence overexpressed under inflammatory conditions. Higher levels of COX-2 expression are closely related to a higher incidence of parametrial invasion and lymph node metastases in early-stage uterine cervical cancer. The principal products of COX-2 enzyme, prostanoids, are released from cells and act locally in autocrine and paracrine modes, activating diverse intracellular pathways, which in turn induce cellular proliferation, antiapoptotic activity, angiogenesis, and increased metastasis. In the current review, we focus on the role of the viral oncogenic proteins in activation of the COX-2/PGE2 pathway and their clinical implications, a better understanding of which would be helpful in designing newer and more effective therapeutic and preventive strategies for the disease.European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 04/2014; 23(5). DOI:10.1097/CEJ.0000000000000023 · 2.76 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Aim: 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic drugs. Resistance to 5-FU is a major cause of chemotherapy failure in advanced-stage hepatocellular carcinoma (HCC). Green tea polyphenol Epigallocatechin-3-gallate (EGCG) plays a critical role in growth inhibition and apoptotic induction in HCC cell lines. The aim of this study is to investigate whether EGCG can enhance 5-FU-induced cell growth inhibition and to explore its potential mechanisms. Methods: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate cell growth. Western blotting analysis was performed to detect the proteins expression in Hep3B cells. Small interfering RNA was used to suppress cyclooxygenase-2 (COX-2) expression. Furthermore, enzyme linked immunosorbent assay was used to test the prostaglandin E(2) (PGE(2) ) production in cell cultures. Results: Epigallocatechin-3-gallate augmented the anti-tumor effect of 5-FU in Hep3B cells. Significant difference was observed between the treated groups and the control group (P < 0.05). EGCG (its concentrations at over 5 µmol/L) combined with 5-FU presented a synergic effect. Furthermore, the combination of EGCG and 5-FU abrogated the COX-2 overexpression and PGE(2) secretion induced by 5-FU. The upregulation of COX-2 expression decreased the phosphorylation of Akt (Thr(308) ) expression. These appeared to be followed by the AMPK hyperactivation. Conclusion: Epigallocatechin-3-gallate sensitizes HCC cells to 5-FU antitumor activity, and the combination of EGCG and 5-FU exhibits synergism in chemo-resistant cancer cells. The results suggest potential novel therapies for the treatment of advanced-stage liver cancer.Hepatology Research 01/2012; 42(5):494-501. DOI:10.1111/j.1872-034X.2011.00947.x · 2.22 Impact Factor