NS-398, a selective cyclooxygenase-2 inhibitor, reduces experimental bladder carcinoma outgrowth by inhibiting tumor cell proliferation

Smakman, Niels; Schaap, Nicoline; Snijckers, Cristel; Rinkes, Inne H.M. Borel; Kranenburg, Onno

doi:10.1016/j.urology.2005.02.024

Cited by 15 publications

(12 citation statements)

References 20 publications

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“…Mice received a single intraperitoneal injection of NS398 (5 mg/kg; Cayman Chemical) after tumor induction (day 0) and three times weekly thereafter for the duration of the experiment. NS398 was prepared as described previously 24. Control mice received the same amount (0.6%) of Dimethylsulfoxid (DMSO) in 750 μl of PBS.…”

Section: Methodsmentioning

confidence: 99%

Cyclooxygenase‐2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells

Muraki

Ohga

Hida

et al. 2011

Intl Journal of Cancer

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Tumor angiogenesis is necessary for solid tumor progression and metastasis. Cyclooxygenase (COX)-2 is known to play an important role in cancer growth and invasion, and it activates the signaling pathways controlling cell proliferation, migration, apoptosis, and angiogenesis. COX-2 is reported to be expressed in many cancer cells. Several studies have reported successful treatment of cancer cells with COX-2 inhibitors (COX-2is). However, the effect of COX-2 inhibition on the tumor endothelium remains to be elucidated. Our study shows that COX-2 is expressed in the vasculature of surgically resected human tumors. To investigate the effects of COX-2 inhibition on the tumor endothelium in vitro, we isolated tumor endothelial cells (TECs) from human melanoma and oral carcinoma xenografts in mice, in which we confirmed that tumor growth was suppressed by inhibiting angiogenesis with the COX-2is NS398. COX-2 mRNA was upregulated in TECs compared to normal endothelial cells (NECs). Cell migration and proliferation were suppressed by NS398 in TECs but not in NECs. The effects of NS398 in vivo were consistent with the in vitro results. The number of CD133 1 /vascular endothelial growth factor receptor-2 1 cells in circulation was significantly suppressed by COX-2 inhibition. In addition, the number of progenitor marker-positive cells decreased in the tumor blood vessels after COX-2i treatment, which suggests that the homing of progenitor cells into the tumor was also blocked. We conclude that NS398 specifically targets both TECs and vascular progenitor cells without affecting NECs.

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Section: Methodsmentioning

confidence: 99%

Cyclooxygenase‐2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells

Muraki

Ohga

Hida

et al. 2011

Intl Journal of Cancer

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“…Mizutani et al found that the selective COX-2 inhibitor (JTE-522) synergistically enhanced -independently of the p53 status -the cytotoxic effect of 5-FU against bladder cancer cells (T24 and HT1197) [36], which both are COX-2 expressing cell lines [37].…”

Section: Cox-2 Protein Expression Determined By Western Blotting and mentioning

confidence: 99%

Enhancement of 5-Fluorouracil Efficacy on High COX-2 Expressing HCA-7 Cells by Low Dose Indomethacin and NS-398 but not on Low COX-2 Expressing HT-29 Cells

Réti

Barna

Pap

et al. 2008

Pathol. Oncol. Res.

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The antiproliferative effect of 5-fluorouracil (5-FU) in the presence of low dose non-steroidal anti-inflammatory drugs (NSAIDs) on high cyclooxygenase-2 (COX-2)-expressing HCA-7 and low COX-2-expressing HT-29 colon carcinoma cell lines was investigated. Pharmacogenetic parameters were studied to characterize the 5-FU sensitivity of the two cell lines. Thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms were determined by PCR analysis. Cell proliferation was measured by SRB assay, cell cycle distribution and apoptosis by FACS analysis. Cyclooxygenase expression was detected by Western blot and also by fluorescence microscopy. Prostaglandin E(2) (PGE(2)) levels were investigated with ELISA kit. The HT-29 cell line was found to be homozygous for TS 2R and 1494ins6 and T homozygous for MTHFR 677 polymorphisms predicting high 5-FU sensitivity (IC(50): 10 microM). TS 3R homozygosity, TS 1496del6 and MTHFR 677CT heterozygosity may explain the modest 5-FU sensitivity (IC(50): 1.1 mM) of the HCA-7 cell line. Indomethacin and NS-398 (10 microM and 1.77 microM, respectively) reduced the PGE(2) level in HCA-7 cells (>90%). Low concentrations of NSAIDs without antiproliferative potency increased the S-phase arrest and enhanced the cytotoxic action of 5-FU only in HCA-7 cells after 48-hours treatment. The presented data suggested that the enhancement of 5-FU cytotoxicity by indomethacin or NS-398 applied in low dose is related to the potency of NSAIDs to modulate the cell-cycle distribution and the apoptosis; however, it seems that this effect might be dependent on cell phenotype, namely on the COX-2 expression.

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“…We also found that over-expression of miR-16 could down-regulate COX-2 expression in bladder cancer cells (Figure 6B). Accumulating evidence suggests an important role for COX-2 in induction of cell proliferation and reduction of apoptosis of bladder cancer cells [10,11,12]. Inhibition of COX-2 activity and/or expression caused reduced cell proliferation and increased apoptosis [29].…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that COX-2 expression levels are up-regulated in bladder cancers cells, which are positively associated with an increased disease stage and with reduced patient survival [10,11]. Up-regulation of COX-2 expression is implicated in stimulation of cancer cell growth and invasion and induction of bladder cancers cell apoptosis [12]. As a result, COX-2 is a promising target and selective COX-2 inhibitors have been evaluated as chemopreventive agents for treatment of bladder cancers [13].…”

Section: Introductionmentioning

confidence: 99%

Artesunate Induces Apoptosis of Bladder Cancer Cells by miR-16 Regulation of COX-2 Expression

Zuo

Wang

Xue

2014

IJMS

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Bladder cancer is the most common malignant tumor of the urinary tract and remains one of the major causes of cancer death worldwide. In this study, we investigated the effect and mechanism of Artesunate (ART), a traditional Chinese medicine, on inducing apoptosis of human bladder cancer cells. In vivo antitumor activity was investigated in bladder cancer in rat by subcutaneous injection of different concentration of ART. The effect of ART on growth inhibition and apoptosis of bladder cancer cells was evaluated using dimethylthiazoly-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis, respectively. Cyclooxygenase-2 (COX-2) and miR-16 expression levels were determined with real-time PCR. The concentrations of prostaglandin E2 (PGE2) in the supernatants of bladder cancer cells were measured with an ELISA kit. The miR-16 inhibitor or mimic were transfected into cells to up- or down-regulate miR-16 expression. ART efficiently inhibited orthotopic tumor growth in the bladder cancer rat, which is accompanied with an increase of miR-16 expression and a decrease of COX-2 expression. In vitro, ART could induce cytotoxicity and apoptosis in bladder cancer cells, but presented a much lighter toxicity effect against normal human urothelial cells. ART significantly increased miR-16 expression and decreased the expression of COX-2 and the production of PGE2. More importantly, down-regulation of miR-16 expression could reverse the effect of ART on apoptosis and COX-2 expression in bladder cells. Moreover, exogenous PGE2 could inhibit apoptosis of bladder cancer cells treated with ART. In conclusion, ART can elicit an anti-tumor effect against bladder cancer by up-regulation of miR-16 expression, which resulted in the decrease of COX-2 expression and PGE2 production. Hence, ART might be an effective drug for the treatment of bladder cancer.

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NS-398, a selective cyclooxygenase-2 inhibitor, reduces experimental bladder carcinoma outgrowth by inhibiting tumor cell proliferation

Cited by 15 publications

References 20 publications

Cyclooxygenase‐2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells

Cyclooxygenase‐2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells

Enhancement of 5-Fluorouracil Efficacy on High COX-2 Expressing HCA-7 Cells by Low Dose Indomethacin and NS-398 but not on Low COX-2 Expressing HT-29 Cells

Artesunate Induces Apoptosis of Bladder Cancer Cells by miR-16 Regulation of COX-2 Expression

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