Tepoxalin
(Synonyms: 替泊沙林) 目录号 : GC49386
A dual inhibitor of COX and 5-LO
Cas No.:103475-41-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Tepoxalin is a dual inhibitor of COX and 5-lipoxygenase (5-LO; IC50s = 2.84 and 0.15 µM, respectively, in RBL-1 cell lysates).1 It also inhibits the activity of 12-, but not 15-, LO (IC50s = 4.45 and 146.6 µM for the human platelet and rabbit reticulocyte enzymes, respectively). Tepoxalin reduces the production of thromboxane B2 and leukotriene B4 induced by the calcium ionophore A23187 in human peripheral blood mononuclear cells (PBMCs; IC50s = 0.01 and 0.07 µM, respectively) and decreases epinephrine-induced platelet aggregation in human platelet-rich plasma (PRP; IC50 = 0.045 µM). It inhibits paw swelling in a rat model of adjuvant-induced arthritis with an ED50 value of 3.5 mg/kg.
1.Argentieri, D.C., Ritchie, D.M., Ferro, M.P., et al.Tepoxalin: A dual cyclooxygenase/5-lipoxygenase inhibitor of arachidonic acid metabolism with potent anti-inflammatory activity and a favorable gastrointestinal profileJ. Pharmacol. Exp. Ther.271(3)1399-1408(1994)
| Cas No. | 103475-41-8 | SDF | |
| 别名 | 替泊沙林 | ||
| Canonical SMILES | ClC(C=C1)=CC=C1C2=CC(CCC(N(O)C)=O)=NN2C3=CC=C(OC)C=C3 | ||
| 分子式 | C20H20ClN3O3 | 分子量 | 385.8 |
| 溶解度 | DMF: 30 mg/ml,DMSO: 30 mg/ml,Ethanol: 15 mg/ml,PBS (pH 7.2): insolu | 储存条件 | -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.592 mL | 12.9601 mL | 25.9202 mL |
| 5 mM | 0.5184 mL | 2.592 mL | 5.184 mL |
| 10 mM | 0.2592 mL | 1.296 mL | 2.592 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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Tepoxalin increases chemotherapy efficacy in drug-resistant breast cancer cells overexpressing the multidrug transporter gene ABCB1
Transl Oncol 2021 Oct;14(10):101181.PMID:34298440DOI:10.1016/j.tranon.2021.101181.
Effective cancer chemotherapy treatment requires both therapy delivery and retention by malignant cells. Cancer cell overexpression of the multidrug transmembrane transporter gene ABCB1 (MDR1, multi-drug resistance protein 1) thwarts therapy retention, leading to a drug-resistant phenotype. We explored the phenotypic impact of ABCB1 overexpression in normal human mammary epithelial cells (HMECs) via acute adenoviral delivery and in breast cancer cell lines with stable integration of inducible ABCB1 expression. One hundred sixty-two genes were differentially expressed between ABCB1-expressing and GFP-expressing HMECs, including the gene encoding the cyclooxygenase-2 protein, PTGS2. Several breast cancer cell lines with inducible ABCB1 expression demonstrated sensitivity to the 5-lipoxygenase, cyclooxygenase-1/2 inhibitor Tepoxalin in two-dimensional drug response assays, and combination treatment of Tepoxalin either with chemotherapies or with histone deacetylase (HDAC) inhibitors improved therapeutic efficacy in these lines. Moreover, selection for the ABCB1-expressing cell population was reduced in three-dimensional co-cultures of ABCB1-expressing and GFP-expressing cells when chemotherapy was given in combination with Tepoxalin. Further study is warranted to ascertain the clinical potential of Tepoxalin, an FDA-approved therapeutic for use in domesticated mammals, to restore chemosensitivity and improve drug response in patients with ABCB1-overexpressing drug-resistant breast cancers.
Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling
Nat Cancer 2020 Feb;1(2):235-248.PMID:32613204DOI:10.1038/s43018-019-0018-6.
Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins; and the anti-inflammatory drug Tepoxalin, which killed via the multi-drug resistance protein ABCB1. The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.
Tepoxalin inhibits inflammation and microvascular dysfunction induced by abdominal irradiation in rats
Aliment Pharmacol Ther 2000 Jun;14(6):841-50.PMID:10848671DOI:10.1046/j.1365-2036.2000.00771.x.
Background: Inflammatory cells contribute to the acute and sub-acute sequelae of radiation therapy. Tepoxalin, an inhibitor of cyclooxygenase and 5-lipoxygenase that suppresses NF-kappaB activation, has potent anti-inflammatory activity. Aims: To assess the effects of Tepoxalin on radiation-induced inflammatory damage, and determine its mechanisms of action. Methods: Leucocyte rolling, adhesion and emigration, and albumin leakage were determined by intra-vital microscopy in rat mesenteric venules. NF-kappaB activation was measured by electrophoretic mobility shift assays, and endothelial intercellular adhesion molecule-1 expression by the radiolabelled antibody technique. Groups of irradiated rats were treated with Tepoxalin, N-acetyl-L-cysteine, zileuton (lipoxygenase inhibitor), or vehicle. Results: Irradiated animals had a marked increase in the number of rolling, adherent and emigrated leucocytes in mesenteric venules, and in microvascular permeability. Tepoxalin prevented leucocyte adhesion and the increase in permeability after radiation. Tepoxalin did not inhibit radiation-induced NF-kappaB activation or intercellular adhesion molecule-1 up-regulation, while N-acetyl-L-cysteine, which attenuated NF-kappaB activation, had no effect on leucocyte recruitment. In contrast, Tepoxalin inhibited the increase in leukotriene B4 levels after radiation, and the anti-inflammatory effects of the drug were mimicked by zileuton. Conclusions: Tepoxalin affords significant protection against radiation-induced inflammation and microvascular dysfunction in splanchnic organs through a mechanism dependent on leukotriene synthesis inhibition.
Tepoxalin, a novel dual inhibitor of the prostaglandin-H synthase cyclooxygenase and peroxidase activities
J Biol Chem 1995 Jun 9;270(23):13948-55.PMID:7775455DOI:10.1074/jbc.270.23.13948.
Prostaglandin-H synthase-1, the rate-limiting enzyme in prostaglandin synthesis, has both cyclooxygenase (CO) and peroxidase (PO) activities. While most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit only the CO activity, we describe an inhibitor, Tepoxalin, that inhibits both the CO (IC50 = 0.1 microM) and the PO (IC50 = 4 microM) activities. Unlike many NSAIDs which are competitive inhibitors of CO, Tepoxalin is a noncompetitive inhibitor of CO and its inhibitory effect on PO but not CO is reversed by excess heme. Moreover, inhibition of the PO activity by Tepoxalin is not dependent on the enzymatic turnover of the CO activity. The hydroxamic acid of Tepoxalin is responsible for the PO inhibition since a carboxylic acid derivative of Tepoxalin retains full CO but not PO inhibition. We postulated that the hydroxamic group might confer the ability to inhibit PO on conventional CO inhibitors. This idea was supported by the observation that naproxen hydroxamic acid, but not naproxen showed PO inhibition. Furthermore, Tepoxalin's carboxylic acid analogue and naproxen each competitively relieved PO inhibition by their respective hydroxamic acids. The intracellular activity of PO as monitored by the release of reactive oxygen species was also inhibited by both Tepoxalin and naproxen hydroxamic acid. These observations suggest a strategy for design of novel compounds to inhibit prostaglandin synthase PO. The therapeutic implications of these novel PO inhibitors are discussed.
An exploration of the ability of Tepoxalin to ameliorate the degradation of articular cartilage in a canine in vitro model
BMC Vet Res 2009 Jul 22;5:25.PMID:19624842DOI:10.1186/1746-6148-5-25.
Background: To study the ability of Tepoxalin, a dual inhibitor of cyclooxygenase (COX) and lipoxygenase (LOX) and its active metabolite to reduce the catabolic response of cartilage to cytokine stimulation in an in vitro model of canine osteoarthritis (OA).Grossly normal cartilage was collected post-mortem from seven dogs that had no evidence of joint disease. Cartilage explants were cultured in media containing the recombinant canine interleukin-1beta (IL-1beta) at 100 ng/ml and recombinant human oncostatin-M (OSM) at 50 ng/ml. The effects of Tepoxalin and its metabolite were studied at three concentrations (1 x 10(-5), 1 x 10(-6) and 1 x 10(-7) M). Total glycosaminoglycan (GAG) and collagen (hydroxyproline) release from cartilage explants were used as outcome measures of proteoglycan and collagen depletion respectively. PGE2 and LTB4 assays were performed to study the effects of the drug on COX and LOX activity. Results: Treatment with IL-1beta and OSM significantly upregulated both collagen (p = 0.004) and proteoglycan (p = 0.001) release from the explants. Tepoxalin at 10(-5) M and 10(-6) M caused a decrease in collagen release from the explants (p = 0.047 and p = 0.075). Drug treatment showed no effect on GAG release. PGE2 concentration in culture media at day 7 was significantly increased by IL-1beta and OSM and treatment with both Tepoxalin and its metabolite showed a trend towards dose-dependent reduction of PGE2 production. LTB4 concentrations were too low to be quantified. Cytotoxicity assays suggested that neither Tepoxalin nor its metabolite had a toxic effect on the cartilage chondrocytes at the concentrations and used in this study. Conclusion: This study provides evidence that Tepoxalin exerts inhibition of COX and can reduce in vitro collagen loss from canine cartilage explants at a concentration of 10(-5) M. We can conclude that, in this model, Tepoxalin can partially inhibit the development of cartilage degeneration when it is available locally to the tissue.