NS 398

NS 398 is a selective inhibitor of cyclooxygenase-2 with IC50 value of 3.8 μM [1].

Cyclooxygenase (COX) is an enzyme that is responsible for the formation of prostaglandins, prostacyclin and thromboxane. COX-2 converts arachidonic acid (AA) to prostaglandin endoperoxide H2.

NS 398 is a selective COX-2 inhibitor and a novel anti-inflammatory agent. NS 398 inhibited COX-2 with IC50 value of 3.8 μM in a concentration-dependent way [1]. In RG/C2, AA/C1 and RR/C1 pre-malignant human colorectal adenoma cell lines, NS-398 (20 ~ 100 μM) inhibited cell proliferation and induced apoptosis. In HT29 colorectal carcinoma cell lines, NS-398 induced apoptosis. Also, NS-398 increased COX-2 protein expression. In HT29 cultures, NS-398 inhibited prostaglandin E2 secretion and COX-2 activity [2].

In rats with trauma, NS-398 (0.3-5 mg/kg) exhibited anti-inflammatory and analgesic effects [1]. In Balb/C mice, NS-398 (10 mg/kg) reduced prostaglandin E2 (PGE2) production and also significantly decreased the production of NO, IL-6 and TNF-α. Also, NS-398 decreased the mRNA levels of COX-2 and inhibited NF-κB activation. These results suggested that NS-398 regulated the inflammatory response after trauma and improved survival [3].

References:
[1].  Futaki N, Takahashi S, Yokoyama M, et al. NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro. Prostaglandins, 1994, 47(1): 55-59.
[2].  Elder DJ, Halton DE, Crew TE, et al. Apoptosis induction and cyclooxygenase-2 regulation in human colorectal adenoma and carcinoma cell lines by the cyclooxygenase-2-selective non-steroidal anti-inflammatory drug NS-398. Int J Cancer, 2000, 86(4): 553-560.
[3].  Mack Strong VE, Mackrell PJ, Concannon EM, et al. NS-398 treatment after trauma modifies NF-kappaB activation and improves survival. J Surg Res, 2001, 98(1): 40-46.

COX-2 inhibitor NS-398 suppresses doxorubicin-induced p53 accumulation through inhibition of ROS-mediated Jnk activation.[Pubmed:26756900]

Mol Carcinog. 2016 Dec;55(12):2156-2167.

Cyclooxygenase-2 (COX-2) is one of the isoforms of cyclooxygenase, a rate-limiting enzyme in the arachidonic acid cascade. COX-2 protein expression is highly induced by numerous factors and it has been reportedly overexpressed in various human malignancies. Although anti-tumorigenic effects of COX-2 inhibitors have been shown, several lines of evidence suggest that COX-2 inhibitors antagonize the cytotoxicity of chemotherapeutic agents. In this study, we investigated the effect of NS-398, a COX-2 inhibitor, on modulation of doxorubicin (DOX)-induced p53 accumulation. Non-selective and selective COX-2 inhibitors attenuated DOX-induced accumulation of wild type (WT) but not mutant p53. Nutlin-3alpha or MG132 abolished the suppressive effect of a COX-2 inhibitor on DOX-induced p53 increase. Moreover, the DOX-induced increase in p53 protein levels was reduced in COX-2 knockout (KO) mouse embryonic fibroblasts (MEFs) compared to those in WT or COX-1 KO MEFs. DOX-induced accumulation of p53 was attenuated by a specific inhibitor or knockdown of Jun-N-terminal kinase (Jnk). In addition, DOX-induced Jnk activation was decreased in COX-2 KO MEFs or by COX-2 inhibition, suggesting that Jnk stabilizes p53 by a mechanism that involves COX-2. Pre-treatment with a reactive oxygen species (ROS) scavenger, N-acetylcysteine, attenuated DOX-induced Jnk activation and subsequent p53 accumulation. Furthermore, the absence or inhibition of COX-2 resulted in suppression of DOX-induced increase in ROS levels. These results suggest that COX-2 activates Jnk through modulation of ROS levels, leading to accumulation of p53. Our study identifies a putative novel cross-talk between COX-2 and p53. (c) 2016 Wiley Periodicals, Inc.

Novel effects of the cyclooxygenase-2-selective inhibitor NS-398 on IL-1beta-induced cyclooxygenase-2 and IL-8 expression in human ovarian granulosa cells.[Pubmed:27312705]

Innate Immun. 2016 Aug;22(6):452-65.

Ovulation is a critical inflammation-like event that is central to ovarian physiology. IL-1beta is an immediate early pro-inflammatory cytokine that regulates production of several other inflammatory mediators, such as cyclooxygenase 2 (COX)-2 and IL-8. NS-398 is a selective inhibitor of COX-2 bioactivity and thus this drug is able to mitigate the COX-2-mediated production of downstream prostaglandins and the subsequent inflammatory response. Here we have investigated the action of NS-398 using a human ovarian granulosa cell line, KGN, by exploring IL-1beta-regulated COX-2 and IL-8 expression. First, NS-398, instead of reducing inflammation, appeared to further enhance IL-1beta-mediated COX-2 and IL-8 production. Using selective inhibitors targeting various signaling molecules, MAPK and NF-kappaB pathways both seemed to be involved in the impact of NS-398 on IL-1beta-induced COX-2 and IL-8 expression. NS-398 also promoted IL-1beta-mediated NF-kappaB p65 nuclear translocation but had no effect on IL-1beta-activated MAPK phosphorylation. Flow cytometry analysis demonstrated that NS-398, in combination with IL-1beta, significantly enhanced cell cycle progression involving IL-8. Our findings demonstrate a clear pro-inflammatory function for NS-398 in the IL-1beta-mediated inflammatory response of granulosa cells, at least in part, owing to its augmenting effect on the IL-1beta-induced activation of NF-kappaB.

NS-398 promotes pancreatic cancer cell invasion by CD147 and MMP-2 via the activation of P38.[Pubmed:26782265]

Mol Med Rep. 2016 Mar;13(3):2208-14.

The overexpression or abnormal activation of cyclooxygenase2 (COX2) has been reported in pancreatic cancer cells. NS398, a selective inhibitor of COX2, is unable to inhibit pancreatic cancer cell proliferation, as determined by a Cell Counting Kit 8 assay. However, it does increase cancer cell invasiveness, and therefore the invasiveness of the PANC1 cells was determined, along with the activation of P38, which was assessed by western blotting. In the present study, to evaluate the mechanisms underlying the action of NS398 in pancreatic cancer cells, PANC1 cells were treated with NS398, and the invasion signaling pathways of cluster of differentiation (CD)147matrix metalloproteinase (MMP)2 and mitogenactivated protein kinases were evaluated. The results showed that NS398induced the expression of CD147 and MMP2 via the activation of P38, which was involved in antiproliferative activity and induced pancreatic cancer cell invasiveness. The PANC1 cells were also cotreated with CD147 small interfering (si)RNA and NS398, and it was found that the NS398induced activation of P38 was not inhibited by CD147 siRNA, however, the expression of MMP2 was inhibited. CD147 siRNA inhibited the invasiveness of the pancreatic cancer cells induced by NS398, but also restored NS398induced antiproliferative activity. These data indicated that P38 in the pancreatic cancer cells was nonspecifically activated by NS398. This activation induced the expression of CD147MMP2, opposed the antiproliferative activity of NS398 and increased the invasiveness of the PANC1 cells.

The COX-2-Selective Antagonist (NS-398) Inhibits Choroidal Neovascularization and Subretinal Fibrosis.[Pubmed:26760305]

PLoS One. 2016 Jan 13;11(1):e0146808.

Choroidal neovascularization (CNV) is an important pathologic component of neovascular age-related macular degeneration (AMD), and CNV lesions later develop into fibrous scars, which contribute to the loss of central vision. Nowadays, the precise molecular and cellular mechanisms underlying CNV and subretinal fibrosis have yet to be fully elucidated. Cyclooxygenase-2 (COX-2) has previously been implicated in angiogenesis and fibrosis. However, the role of COX-2 in the pathogenesis of CNV and subretinal fibrosis is poorly understood. The present study reveals several important findings concerning the relationship of COX-2 signaling with CNV and subretinal fibrosis. Experimental CNV lesions were attenuated by the administration of NS-398, a COX-2-selective antagonist. NS-398-induced CNV suppression was found to be mediated by the attenuation of macrophage infiltration and down-regulation of VEGF in the retinal pigment epithelium-choroid complex. Additionally, NS-398 attenuated subretinal fibrosis, in an experimental model of subretinal scarring observed in neovascular AMD, by down-regulation of TGF-beta2 in the retinal pigment epithelium-choroid complex. Moreover, we cultured mouse RPE cells and found that NS-398 decreased the secretion of VEGF and TGF-beta2 in mouse RPE cells. The results of the present study provide new findings regarding the molecular basis of CNV and subretinal fibrosis, and provide a proof-of-concept approach for the efficacy of COX-2 inhibition in treating subretinal fibrosis.

The MEK/ERK pathway mediates COX-2-selective NSAID-induced apoptosis and induced COX-2 protein expression in colorectal carcinoma cells.[Pubmed:11992399]

Int J Cancer. 2002 May 20;99(3):323-7.

Nonsteroidal antiinflammatory drugs (NSAIDs) can prevent colorectal tumorigenesis in humans and in rodents. In vitro and in vivo studies indicate that one of their principal antineoplastic avenues is the induction of apoptosis. We have shown previously that NS-398, which selectively inhibits cyclooxygenase-2 (COX-2) over cyclooxygenase-1, induces apoptosis of colorectal tumour cells and elevates COX-2 protein expression. Here, we have determined that the extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway mediates these effects of NS-398. Treatment of HT29 colorectal carcinoma cells with 75 microM NS-398 caused activation of ERK-1/-2 but not of the p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. This was apparent at 24 hr and maintained at 72 hr. U0126, a specific inhibitor of the ERK-activating kinases MEK-1/-2, prevented the activation of ERK induced by NS-398 and blocked the increase in COX-2 protein expression seen when HT29 cells were treated with NS-398 alone. The activation of ERK by NS-398 preceded and accompanied a decrease in attached cell yield and an increase in apoptosis. U0126 dose-dependently protected HT29 cells from these antiproliferative effects of NS-398, indicating an antiproliferative role for sustained ERK-1/-2 activation in response to this NSAID. These results point to a key role for the MEK/ERK signalling pathway in mediating the effects of a COX-2-selective NSAID on colorectal carcinoma cells.

NS-398, a novel non-steroidal anti-inflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions.[Pubmed:8482483]

Gen Pharmacol. 1993 Jan;24(1):105-10.

1. NS-398 (N-[2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide) is a new non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic effects. 2. The anti-inflammatory potency of NS-398 in rat carrageenin-induced edema was as potent as that of indomethacin and 8 times more potent than diclofenac. In rat adjuvant arthritis, NS-398 showed a therapeutic effect comparable to that seen with loxoprofen but less than that seen with indomethacin and diclofenac. 3. The analgesic potency of NS-398 in rat adjuvant arthritic pain was much the same as that of indomethacin, and was about 3-5 times higher than that of diclofenac and loxoprofen. In the Randall-Selitto method in rats, NS-398 was 2-7 times as potent as loxoprofen, diclofenac and indomethacin. In acetic acid-induced writhing in mice, NS-398 was equipotent to indomethacin and diclofenac. 4. In LPS-induced fever in rats, NS-398 was 1.5-4.5 times as potent as loxoprofen and indomethacin, but less potent than diclofenac. 5. NS-398 produced little gastric ulceration in doses of up to 1000 mg/kg, while reference drugs produced distinct stomach lesions in doses of 10-30 mg/kg. 6. NS-398 inhibited prostaglandin (PG) endoperoxide synthase from sheep seminal vesicle microsomes less potent than that of ibuprofen.

NS-398 is a non-steroidal an-inflammatory agent with analgesic and antipyretic effects, and selectively inhibits prostaglandin G/H synthase 2/cyclooxygenase 2 (COX-2) activity, with an IC50 of 3.8 μM, and has no effect on COX-1 at 100 μM.

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