PD98059 is a potent and selective MEK inhibitor with an IC50 of 2 μM. PD98059 binds to the inactive form of MEK, thereby preventing the upstream kinase from activating MEK1/2. Besides, PD98059 is a ligand for the AHR and functions as an AHR antagonist[1-3].
PD98059(10 μM PD98059;14days) combined with TGF-β1 transforms human UDSCs (hUDSCs) into smooth muscle cells (SMCs)[4]. PD98059 (10 μM PD98059 ;24 h) suppresses the ERK pathway and the epithelial mesenchymal transition process(EMT) process in low dose cisplatin-resistant ovarian cancer cells(SKOV-3/DDP) [5]. PD98059 arrested Hec50co cells at the G0/G1 phase, the combination with PTX treatment increased accumulation at both the G0/G1 and G2/M phase[6]. PD98059(1, 5, 10, 20 and 50 μM；24h) inhibited MCF-7 and MDA-MB-231 cells proliferation in a dose-dependent manner[7].
PD98059(5 mg/kg/day; i.p; 2 weeks) treatment reduced adverse effects, including micronucleus (MN) formation, lipid peroxidation, and glutathione(GSH) oxidation in the EAE model[8].PD98059(0.15/0.3mg/kg PD98059; i.v. gtt) protects the brain against mitochondrial-mediated apoptosis and autophagy at 24 h post-resuscitation in rats subjected to cardiac arrest/cardiopulmonary resuscitation (CA/CPR), which is linked with the downregulation of dynamin-related protein 1 (Drp1) expression[9]. Treatment of mice with PD98059(10mg/kg; i.p; bolus) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan[10].
D98059是一种有效的选择性MEK抑制剂，IC50为2 μM。PD98059结合无活性形式的MEK，从而阻止上游激酶激活MEK1/2。此外，PD98059是AHR的配体，具有AHR拮抗剂的功能[1-3]。
PD98059(10 μM PD98059;14days)结合TGF-β1可将人尿源干细胞HUDSCs转化为平滑肌细胞(SMCs) [4]。PD98059 (10 μM PD98059 ;24 h)抑制低剂量顺铂耐药卵巢癌细胞(SKOV-3/DDP)的ERK通路和上皮间充质转化EMT过程[5]。PD98059在G0/G1期阻滞了Hec50co细胞，与PTX联合处理增加了G0/G1和G2/M期的积累[6]。PD98059(1、5、10、20 and 50μM;24h)呈剂量依赖性抑制MCF-7和MDA-MB-231细胞的增殖[7]。
在EAE模型中，PD98059(5 mg/kg/day; i.p; 2 weeks)治疗减少了不良反应，包括微核(MN)形成、脂质过氧化和谷胱甘肽(GSH)氧化[8]。在心脏骤停/心肺复苏(CA/CPR)大鼠复苏后24小时，PD98059(0.15/0.3mg/kg PD98059; i.v. gtt)保护大脑免受线粒体介导的细胞凋亡和自噬，这与动力蛋白相关蛋白1 (Drp1)表达下调有关[9]。用PD98059(10mg/kg; i.p; bolus)治疗小鼠可减少由zymosan酶引起的腹膜渗出和多形核细胞的迁移[10]。
参考文献:
[1]. Reiners JJ Jr, Lee JY, Clift RE, et.al. PD98059 is an equipotent antagonist of the aryl hydrocarbon receptor and inhibitor of mitogen-activated protein kinase kinase. Mol Pharmacol. 1998 Mar;53(3):438-45. doi: 10.1124/mol.53.3.438. PMID: 9495809.
[2]. Dudley DT, Pang L, et.al. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686-9. doi: 10.1073/pnas.92.17.7686. PMID: 7644477; PMCID: PMC41210.
[3]. Attia SM, Ahmad SF, et.al.The MAP kinase inhibitor PD98059 reduces chromosomal instability in the autoimmune encephalomyelitis SJL/J-mouse model of multiple sclerosis. Mutat Res Genet Toxicol Environ Mutagen. 2021 Jan-Feb;861-862:503278. doi: 10.1016/j.mrgentox.2020.503278. Epub 2020 Oct 29. PMID: 33551096.
[4]. Hwang Y, Cha SH, et.al.Combination of PD98059 and TGF-β1 Efficiently Differentiates Human Urine-Derived Stem Cells into Smooth Muscle Cells. Int J Mol Sci. 2021 Sep 29;22(19):10532. doi: 10.3390/ijms221910532. PMID: 34638875; PMCID: PMC8508912.
[5]. Hou L, Hou X, et.al.PD98059 impairs the cisplatin-resistance of ovarian cancer cells by suppressing ERK pathway and epithelial mesenchymal transition process. Cancer Biomark. 2017 Dec 12;21(1):187-194. doi: 10.3233/CBM-170644. PMID: 29103028.
[6].Wiwatchaitawee K, Mekkawy AI, et.al. The MEK 1/2 inhibitor PD98059 exhibits synergistic anti-endometrial cancer activity with paclitaxel in vitro and enhanced tissue distribution in vivo when formulated into PAMAM-coated PLGA-PEG nanoparticles. Drug Deliv Transl Res. 2022 Jul;12(7):1684-1696. doi: 10.1007/s13346-021-01065-7. Epub 2021 Oct 11. PMID: 34635984; PMCID: PMC8995400.
[7]. Zhao Y, Ge CC, et.al. MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation. Oncol Rep. 2017 Nov;38(5):3055-3063. doi: 10.3892/or.2017.5955. Epub 2017 Sep 13. PMID: 29048617.
[8]. Attia SM, Ahmad SF, et.al.The MAP kinase inhibitor PD98059 reduces chromosomal instability in the autoimmune encephalomyelitis SJL/J-mouse model of multiple sclerosis. Mutat Res Genet Toxicol Environ Mutagen. 2021 Jan-Feb;861-862:503278. doi: 10.1016/j.mrgentox.2020.503278. Epub 2020 Oct 29. PMID: 33551096.
[9]. Zheng JH, Xie L, et.al. PD98059 protects the brain against mitochondrial-mediated apoptosis and autophagy in a cardiac arrest rat model. Life Sci. 2019 Sep 1;232:116618. doi: 10.1016/j.lfs.2019.116618. Epub 2019 Jun 29. PMID: 31265854.
[10].Di Paola R, Galuppo M, et.al.PD98059, a specific MAP kinase inhibitor, attenuates multiple organ dysfunction syndrome/failure (MODS) induced by zymosan in mice. Pharmacol Res. 2010 Feb;61(2):175-87. doi: 10.1016/j.phrs.2009.09.008. Epub 2009 Oct 9. PMID: 19819333.
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Kinase activity Assay[1]： |
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Preparation method |
Incorporation of 32P into myelin basic protein (MBP) was assayed in the presence of glutathione S-transferase (GST) fusion proteins containing the 44-kDa MAPK (GST-MAPK) or the 45-kDa MEK (GST-MEK1) with(or not) PD98059. Assays were conducted in 50 μl of 50 mM Tris, pH 7.4，10 mM MgCl2，2 mM EGTA，10 μM [y-32P]ATP containing 10 μg of GST-MEK1, 0.5 μg of GST-MAPK, and 40 μg of MBP. After incubation at 30℃ for 15 min, reactions were stopped by addition of Laemmli SDS sample buffer. Phosphorylated MBP was resolved by SDS/PAGE(10%). |
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Applications |
D98059 is a non-ATP-competitive MEK inhibitor with an IC50 of 2 μM. |
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Cell experiment [2]: |
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Cell lines |
MCF-7 and MDA-MB-231 cells |
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Preparation method |
Cells were seeded in 96-well plates. After cells grew to 30% of the bottom of cell culture plates, various concentrations of PD980589 (1, 5, 10, 20 and 50 μM) were added to the cells and incubation was carried out for 24 h. |
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Reaction Conditions |
1, 5, 10, 20 and 50 μM；24h |
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Applications |
PD98059 inhibited MCF-7 and MDA-MB-231 cells proliferation in a dose-dependent manner. |
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Animal experiment [3]: |
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Animal models |
SJL/J mice (experimental autoimmune encephalomyelitis (EAE) model) |
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Preparation method |
Mice received a single daily intraperitoneal injection of PD98059, or sham with equal amounts of 1% DMSO, once they reached a neurological disability score of >2 (i.e., day 14). Mice were euthanized 24 h after the last injection with PD98059, and bone marrow cells and spinal cord tissues were harvested. |
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Dosage form |
5 mg/kg/day; i.p; 2 weeks |
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Applications |
PD98059 treatment reduced adverse effects, including micronucleus (MN) formation, lipid peroxidation, and glutathione (GSH) oxidation in the EAE model. |
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参考文献: [1]. Dudley DT, Pang L, et.al. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686-9. doi: 10.1073/pnas.92.17.7686. PMID: 7644477; PMCID: PMC41210. [2]. ?Zhao Y, Ge CC, et.al.MEK inhibitor, PD98059, promotes breast cancer cell migration by inducing β-catenin nuclear accumulation. Oncol Rep. 2017 Nov;38(5):3055-3063. doi: 10.3892/or.2017.5955. Epub 2017 Sep 13. PMID: 29048617. [3]. Attia SM, Ahmad SF, et.al. The MAP kinase inhibitor PD98059 reduces chromosomal instability in the autoimmune encephalomyelitis SJL/J-mouse model of multiple sclerosis. Mutat Res Genet Toxicol Environ Mutagen. 2021 Jan-Feb;861-862:503278. doi: 10.1016/j.mrgentox.2020.503278. Epub 2020 Oct 29. PMID: 33551096. |
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