Indomethacin (Indometacin) is a potent, orally active COX1/2 inhibitor with IC50 values of 18 nM and 26 nM for COX-1 and COX-2, respectively. Indomethacin has anticancer activity and anti-infective activity. Indomethacin can be used for cancer, inflammation and viral infection research[1-3].
Indomethacin(24 hours) significantly inhibited 3LL-D122 cell viability at 20 μM, with 50% inhibition at approx. 60 μM[2]. Indomethacin(1 or 10 uM of indomethacin)can suppress HT29 cancer cell migration through its influence on the focal complexes formation [4]. Indomethacin(1.54 μg/ml)during mitosis did not interfere with the M/G1 progression in synchronized BY-2 cells but it inhibited cAMP production at the beginning of the G1 phase and arrested the cell cycle progression at G1/S in tobacco bright yellow 2 (TBY-2) cell [5]. Inhibition of PGE2 production by indomethacin (50 mM;3days) eliminated the macrophage suppression factor from the supernatant, and sensitized the resistant tumor cells (NIH3T3 or M109 cells) to macrophage cytotoxicity [6].
Indomethacin given at a concentration of 10 μg/mL in the drinking water (calculated to be approx. 2 mg/kg/day) inhibited platelet COX-1 (thromboxane B2 formation) by >95% and significantly delayed the onset of tumor growth and the initial growth rate of the footpad tumors[2]. Indomethacin(30 mg/kg；p.o.；3-12h)can induce time-dependent apoptotic and autophagic cell death of gastric parietal cells (PCs) in mice[7]. Indomethacin(1 mg/kg for 28 days) by itself had no effect on tumor growth kinetics, nor did it improve the transient antitumor effect of Cyclophosphamide (CTX). However, the addition of indomethacin significantly enhanced the efficacy of mCD19CAR T therapy[8].
Indomethacin(吲哚美辛)是一种有效的口服活性 COX1/2 抑制剂,COX-1 和 COX-2 的IC50 值分别为 18 nM 和 26 nM。同时,Indomethacin具有抗癌和抗感染活性,可用于癌症、炎症和病毒感染的研究[1-3]。
Indomethacin在20 μM(24h)时显著抑制细胞活力,浓度为60μM时抑制能力约为50% [2]。Indomethacin (1或10 uM)可通过影响局灶复合物形成抑制HT29癌细胞迁移[4]。Indomethacin (1.54 μg/ml)在有丝分裂时对BY-2细胞的M/G1进程无干扰作用,但在G1期开始时抑制cAMP的产生,并在G1/S期阻断细胞周期进程[5]。Indomethacin (50 mM;3天)抑制PGE2的产生,清除了上清液中的巨噬细胞抑制因子,并使耐药肿瘤细胞(NIH3T3或M109细胞)对巨噬细胞敏感[6]。
Indomethacin以10 μg/mL的浓度加于饮用水中(约为2 mg/kg/day)可抑制血小板COX-1的程度为95%,显著延缓肿瘤的发生和足底肿瘤的初始生长速度[2]。Indomethacin (30mg /kg;p.o;3-12h)可诱导小鼠胃壁细胞(PCs)时间依赖性凋亡和自噬细胞死亡[7]。Indomethacin (1 mg/kg, 28days)本身对肿瘤生长动力学没有影响,也没有改善环磷酰胺(CTX)的瞬时抗肿瘤作用。然而,Indomethacin的加入显著增强了mCD19CAR - T治疗的疗效[8]。
参考文献:
[1]. Riendeau D, Percival MD, et al. Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol. 1997 May;121(1):105-17. doi: 10.1038/sj.bjp.0701076. PMID: 9146894; PMCID: PMC1564640.
[2]. Eli Y, Przedecki F, et al. Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo. Biochem Pharmacol. 2001 Mar 1;61(5):565-71. doi: 10.1016/s0006-2952(00)00578-5. PMID: 11239499.
[3]. Amici C, La Frazia S, et al. Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: role of eIF2α kinase PKR. Cell Microbiol. 2015 Sep;17(9):1391-404. doi: 10.1111/cmi.12446. Epub 2015 May 13. PMID: 25856684; PMCID: PMC7162271.
[4]. Guo YC, Chang CM, et al.Indomethacin inhibits cancer cell migration via attenuation of cellular calcium mobilization. Molecules. 2013 Jun 4;18(6):6584-96. doi: 10.3390/molecules18066584. PMID: 23736792; PMCID: PMC6269835.
[5]. Ehsan H, Roef L, et al.Indomethacin-induced G1/S phase arrest of the plant cell cycle. FEBS Lett. 1999 Sep 24;458(3):349-53. doi: 10.1016/s0014-5793(99)01152-7. PMID: 10570938.
[6]. Totary-Jain H, et al. Indomethacin sensitizes resistant transformed cells to macrophage cytotoxicity. Immunol Lett. 2016 Aug;176:1-7. doi: 10.1016/j.imlet.2016.05.011. Epub 2016 May 17. PMID: 27210423; PMCID: PMC6011832.
[7]. Gebril SM, Ito Y, et al. Indomethacin can induce cell death in rat gastric parietal cells through alteration of some apoptosis- and autophagy-associated molecules. Int J Exp Pathol. 2020 Dec;101(6):230-247. doi: 10.1111/iep.12370. Epub 2020 Sep 28. PMID: 32985762; PMCID: PMC7691216.
[8]. Aboelella NS, Brandle C, et al.Indomethacin-induced oxidative stress enhances death receptor 5 signaling and sensitizes tumor cells to adoptive T-cell therapy. J Immunother Cancer. 2022 Jul;10(7):e004938. doi: 10.1136/jitc-2022-004938. PMID: 35882449; PMCID: PMC9330341.
| Cell experiment [1]: | |
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Cell lines |
3LL-D122 cells ( Lewis lung carcinoma cells) |
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Preparation Method |
Recombinant human COX-1 and COX-2 were expressed in Sf-9 cells and purified. Enzymatic activity was measured by use of a chromogenic assay based on the oxidation of N,N,N',N -tetramethyl-p-phenylenediamine (TMPD) during the reduction of PGG2 to PGH2. The assay mixture (180 μl) contains 100 mM sodium phosphate, pH 6.5, 1 μM hematin, 1 mg ml-1 gelatin, 80-100 units of purified enzyme (one unit of enzyme is defined as the amount of enzyme required to produce an O.D. change of 0.001 min-1 at 610 nm) and 4 μl of the test compound( indomethacin ) in dimethylsulphoxide (DMSO). The mixture was preincubated at room temperature (22℃) for 15 min before initiation of the enzymatic reaction by the addition of 20 μl of a solution of 1 mM arachidonic acid and 1 mm TMPD in assay buffer (without enzyme or hematin). The enzyme activity was measured by estimation of the initial velocity of TMPD oxidation over the first 36 s of the reaction. A non-specific rate of oxidation was observed in the absence of enzyme (0.007-0.01 O.D. min-1) and was subtracted before the calculation of the % inhibition. IC50 values were derived from the 4-parameter least squares non-linear regression analysis of the log-dose vs % inhibition plot. For measurement of COX-2 peroxidase activity, the reaction was initiated by the addition of 20 μl of a solution of 4 mM hydrogen peroxide and 0.5 mM TMPD in assay buffer. |
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Reaction Conditions |
0, 20, 50, 100 and 150μM；24 hours |
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Applications |
Indomethacin was a potent inhibitor of both COX-1 ( IC50=18±3 nM) and COX-2 ( IC50=26±6 nM). |
| Animal experiment [2]: | |
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Animal models |
Male C57BL/6J mice(8-10 weeks)(carried LL(Lewis lung) carcinoma cells) |
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Preparation Method |
Indomethacin (prepared as a 100X stock of 1 mg/mL in 0.25 M Tris-HCI, pH = 8.5) was added in the drinking water at a final concentration of 10 μg/mL. |
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Dosage form |
Mice were given drinking water containing 10 μg/mL( approx 2mg/kg/day) of indomethacin beginning one day before inoculation with LL carcinoma cells and continuing until the termination of the experiment. |
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Applications |
Indomethacin given at a concentration of 10 μg/mL in the drinking water inhibited platelet COX-1 (thromboxane B2 formation) by >95% and significantly delayed the onset of tumor growth and the initial growth rate of the footpad tumors. |
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参考文献: [1]. Riendeau D, Percival MD, et al. Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol. 1997 May;121(1):105-17. doi: 10.1038/sj.bjp.0701076. PMID: 9146894; PMCID: PMC1564640. |
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