NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro

Futaki, Nobuko; Takahashi, Satoru; Yokoyama, Motofumi; Arai, Iwao; Higuchi, Shu; Otomo, Susumu

doi:10.1016/0090-6980(94)90074-4

Cited by 767 publications

(402 citation statements)

References 18 publications

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“…Although HTLV-I Tax transactivated the COX-2 promoter in a T-cell line, Tax did not induce COX-2 mRNA expression. We also showed that NS398, a selective COX-2 inhibitor, 18 inhibited cell proliferation and induced apoptosis in HTLV-I-infected T-cell lines. The NS398-induced apoptosis in HTLV-I-infected T cells was associated with downregulation of Bcl-2 and Bcl-x L expression.…”

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confidence: 66%

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Constitutive expression of the cyclooxygenase-2 gene in T-cell lines infected with human T cell leukemia virus type I

Mori

Inoue

Yoshida³

et al. 2001

Int. J. Cancer

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Cyclooxygenase-2 (COX-2), an inducible enzyme that catalyzes the formation of prostaglandins and other eicosanoids from arachidonic acid, is constitutively expressed in several human carcinomas. COX-2 expression, however, has not been extensively studied in leukemia. Human T cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia, an aggressive form of human T cell malignancy. We studied COX-2 mRNA expression in various human Tcell lines. Northern blot analysis revealed that COX-2 mRNA steady-state levels were high in 4 of 7 T-cell lines infected with HTLV-I. COX-2 mRNA, however, was not expressed in any of 3 HTLV-I-negative T-cell lines. We also confirmed COX-2 expression in 6 of 7 HTLV-I-positive T-cell lines by reverse transcription-PCR. HTLV-I Tax is known to increase the expression of cellular genes and thus we assayed Tax for its ability to increase transcription from the COX-2 promoter. Although Tax increased transcription of the COX-2 promoter in a T-cell line, Tax expression did not induce COX-2 mRNA expression, indicating that Tax alone is not sufficient for significant accumulation of COX-2 mRNA, which probably requires an additional viral protein. To evaluate the potential role of COX-2 in T cells, the HTLV-Iinfected T-cell lines were treated with NS398, a selective COX-2 inhibitor. NS398 treatment inhibited proliferation and induced apoptosis of HTLV-I-infected T-cell lines and downregulated Bcl-2 and Bcl-x L mRNA expression, followed by chromosomal DNA fragmentation. Our data suggest that COX-2 is expressed selectively in T-cell lines infected with HTLV-I and that this gene may play a role in cell survival.

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confidence: 66%

“…36,37 NS398 has been reported to have high selectivity for COX-2. 18 Thus, we examined the effect of NS398 on growth of HTLV-I-infected T cells. We used the C5/MJ and HUT-102 cell lines as both exhibited the strongest expression of COX-2 when analyzed by Northern blot (Fig.…”

Section: Inhibition Of Cell Proliferation and Apoptosis Induced By A mentioning

confidence: 99%

Constitutive expression of the cyclooxygenase-2 gene in T-cell lines infected with human T cell leukemia virus type I

Mori

Inoue

Yoshida³

et al. 2001

Int. J. Cancer

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“…N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulphonamide (NS-398) is a sulfonamide derivative that inhibits COX-2 specifically with an IC 50 of 30 nM. It does not affect COX-1 enzyme activity at concentrations exceeding 100 mM, and it inhibits COX-1 dependent prostanoid production only minimally even at doses 4200 mg kg 71 (Futaki et al, 1994;Gierse et al, 1995). The results of these studies suggest the possibility of a functional relationship between gastrin and COX-2 expression and demonstrate that COX-2 selective inhibition is capable of reversing the trophic properties of growth on colorectal adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer

et al. 2002

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Gastrin is a gastrointestinal peptide that possesses potent trophic properties on both normal and neoplastic cells of gastrointestinal origin. Previous studies have indicated that chronic hypergastrinaemia increases the risk of colorectal cancer and cancer growth and that interruption of the effects of gastrin could be a potential target in the treatment of colorectal cancer. Here we demonstrate that gastrin leads to a dose-dependent increase in colon cancer cell proliferation and tumour growth in vitro and in vivo, and that this increment is progressively reversed by pretreatment with the cyclo-oxygenase-2 inhibitor NS-398. Gastrin was able to induce cyclo-oxygenase-2 protein expression, as well as the synthesis of prostaglandin E 2 , the major product of cyclo-oxygenase. Moreover, gastrin leads to approximately a two-fold induction of cyclo-oxygenase-2 promoter activity in transiently transfected cells. The results of these studies demonstrate that cyclo-oxygenase-2 appears to represent one of the downstream targets of gastrin and that selective cyclo-oxygenase-2 inhibition is capable of reversing the trophic properties of gastrin and presumably might prevent the growth of colorectal cancer induced by hypergastrinaemia.

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“…NS-398, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulphonamide, is a sulphonamide derivative that inhibits COX-2 specifically, with an IC 50 of 30 nM. This agent does not affect COX-1 activity at concentrations exceeding 100 mM, and it inhibits COX-1 prostanoid production only minimally, even at a dose exceeding 200 mg kg À1 (Futaki et al, 1994;Gierse et al, 1995). NS-398 can inhibit either chemically induced tumorigenesis in the colon or human cancer xenograft in nude mice (Yoshimi et al, 1997(Yoshimi et al, , 1999Sawaoka et al, 1998).…”

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confidence: 99%

Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer

et al. 2004

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to reduce the risk and mortality of colorectal cancer (CRC) by inhibiting the activity of cyclooxygenase (COX). The present studies were directed to determine whether selective COX-2 inhibition reduces CRC tumour cell proliferation and invasion/migration, and the possible cellular and molecular mechanisms involved. The MC-26 cells are a highly invasive mouse CRC cell line expressing COX-2 protein. NS-398 (100 mM), a highly selective COX-2 inhibitor, decreased cell proliferation by B35% of control, as determined using [ 3 H]-thymidine incorporation. This reduction in cell proliferation was associated with decreased expression of cyclin D1 and proliferating cell nuclear antigen (PCNA). Furthermore, NS-398 inhibited cell invasion/migration through Matrigel extracellular matrix components at 24 h by B60%. The addition of exogenous prostaglandin E 2 partially attenuated the inhibition of cell invasion by 10 mM NS-398, but failed to reverse the effect of 100 mM NS-398. Matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) are two enzymes that facilitate cell invasion/migration by degrading the extracellular matrix. In the presence of 100 mM NS-398, Western blot hybridisation analysis and zymography demonstrated that both MMP-2 and MMP-9 protein levels and enzyme activity were decreased by B25 -30%. In separate studies, NS-398 also inhibited tumour growth in vivo and retarded the formation of liver metastasis. The results of these studies indicate that the expression and activity of COX-2 appear to be associated with both the proliferative and invasive properties of CRC. Cyclooxygenase-2 inhibition suppresses tumour cell growth and invasion/migration, and retards liver metastasis in a mouse colon cancer model, via multiple cellular and molecular mechanisms.

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NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro

Cited by 767 publications

References 18 publications

Constitutive expression of the cyclooxygenase-2 gene in T-cell lines infected with human T cell leukemia virus type I

Constitutive expression of the cyclooxygenase-2 gene in T-cell lines infected with human T cell leukemia virus type I

COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer

Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer

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