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Usage

Uses

Used in Pharmaceutical Industry:
ANTI-EAPII (TTRAP) is used as a target for drug development for the treatment of various diseases, including cancer and inflammatory disorders. Its role in the regulation of NF-κB signaling makes it a potential therapeutic target for modulating immune responses and inhibiting tumor growth.
Used in Research Applications:
ANTI-EAPII (TTRAP) is used as a research tool for studying the molecular mechanisms of cell growth, differentiation, and survival. It can be employed in various experimental setups, such as gene knockdown or overexpression studies, to investigate its function and interactions with other cellular components.
Used in Diagnostic Applications:
ANTI-EAPII (TTRAP) can be used as a biomarker for the diagnosis and prognosis of certain diseases, including cancer. Its expression levels can provide valuable information on the disease progression and response to treatment, aiding in the development of personalized medicine strategies.

Background

(R)-(+)-Etomoxir sodium salt is an irreversible inhibitor of carnitine palmitoyltransferase 1(CPT-1). Etomoxir (100 μM) has no effect on T cells cultured in high glucose. In contrast, there is a significant increase in apoptosis in etomoxir-treated cultures stimulated with antigen under low glucose conditions. C57BL/6 mice treated with Etomoxir (15 mg/kg, i.p) reduce the infiltration of immune cells in the central nervous system. Only a small number of macrophages, activated microglia or T cells are present, while reducing the inflammatory response and Demyelinating reaction.

In Vitro

(R)-(+)-Etomoxir sodium salt is R-form of Etomoxir sodium salt. Etomoxir binds irreversibly to the catalytic site of CPT-1 inhibiting its activity, but also upregulates fatty acid oxidation enzymes. Etomoxir is developed as an inhibitor of the mitochondrial carnitine palmitoyltransferase-1 (CPT-1) located on the outer mitochondrial membrane. Etomoxir, in the liver can act as peroxisomal proliferator, increasing DNA synthesis and liver growth. Thus, etomoxir, in addition of being a CPT1 inhibitor could be considered as a PPARalpha agonist. Etomoxir is a member of the oxirane carboxylic acid carnitine palmitoyl transferase I inhibitors and has been suggested as a therapeutic agent for the treatment of heart failure. Acute Etomoxir treatment irreversibly inhibits the activity of carnitine palmitoyltransferase I. As a result, fatty acid import into the mitochondria and β-oxidation is reduced, whereas cytosolic fatty acid accumulates and glucose oxidation is elevated. Prolonged incubation (24 h) with Etomoxir produces diverse effects on the expression of several metabolic enzyme.

In Vivo

(R)-(+)-Etomoxir sodium salt is R-form of Etomoxir sodium salt. Etomoxir is an inhibitor of free fatty acid (FFA) oxidation-related key enzyme CPT1. P53 interacts directly with Bax, which is inhibited by Etomoxir, further confirming the direct interaction of P53 and Bax, and the involvement of FAO-mediated mitochondrial ROS generation in db/db mice. Rats are injected daily with Etomoxir, a specific CPT-I inhibitor, for 8 days at 20 mg/kg of body mass. Etomoxir-treated rats display a 44% reduced cardiac CPT-I activity. The treatment of Lewis rats for 8 days with 20 mg/kg Etomoxir does not alter blood glucose, which is in line with comparable etomoxir-feeding studies. Similarly, Etomoxir feeding does not affect general growth characteristics such as gain in body mass, nor does it affect hindlimb muscle mass. However, heart mass and liver mass are both significantly increased by 11% in Etomoxir-treated rats.

References

1. Rupp H, et al. The use of partial fatty acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure. Herz. 2002 Nov;27(7):621-36 2. Xu FY, et al. Etomoxir mediates differential metabolic channeling of fatty acid and glycerol precursors into cardiolipin in H9c2 cells. J Lipid Res. 2003 Feb;44(2):415-23 3. Li J, et al. FFA-ROS-P53-mediated mitochondrial apoptosis contributes to reduction of osteoblastogenesis and bone mass in type 2 diabetes mellitus. Sci Rep. 2015 Jul 31;5:12724 4. Luiken JJ, et al. Etomoxir-induced partial carnitine palmitoyltransferase-I (CPT-I) inhibition in vivo does not alter cardiac long-chain fatty acid uptake and oxidation rates. Biochem J. 2009 Apr 15;419(2):447-55. 5. Rupp H, Zarain-Herzberg A, Maisch B. The Use of Partial Fatty Acid Oxidation Inhibitors for Metabolic Therapy of Angina Pectoris and Heart Failure. Herz, 2002, 27(7): 621-636. 6. Shriver L P, Manchester M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Scientific Reports, 2011, 1.

References

1) Agius et al. (1991), Stereospecificity of the inhibition of etomoxir of fatty acid and cholesterol synthesis in isolated rat hepatocytes; Biochem. Pharmacol. 42 1717 2) Lionetti et al. (2011), Modulating fatty acid oxidation in heart failure; Cardiovasc. Res, 90 202 3) Huebinger et al. (1997), Effects of the carnitine-acyltransferase inhibitor etomoxir on insulin sensitivity, energy expenditure, and substrate oxidation in NIDDM; Horm. Metab. Res.?29 436 4) Pike et al. (2011), Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells; Biochim. Biophys. Acta 1807 726 5) Samudio et al. (2010), Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction; J. Clin. Invest. 120 142 6) O’Connor et al. (2018), The CPT1a inhibitor, etomoxir, induces severe oxidative stress at commonly used concentrations; Sci. Rep.?8 6289 7) Yao et al. (2018), Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation; PLoS Biol. 16 e2003782

Biochem/physiol Actions

Irreversible O-carnitine palmitoyltransferase-1 (CPT-1) inhibitor; PPARα activator

InChI:InChI=1/C15H19ClO4.Na.H2O/c16-12-5-7-13(8-6-12)19-10-4-2-1-3-9-15(11-20-15)14(17)18;;/h5-8H,1-4,9-11H2,(H,17,18);;1H2/q;+1;/p-1/t15-;;/m1../s1