PD98059

Biological Activity

PD98059 is an equipotent antagonist of the aryl hydrocarbon receptor and inhibitor of mitogen-activated protein kinase kinase. MEK/ERK pathways are frequently activated in acute myelogenous leukemia, and this signal pathway's inhibitor has made it an interesting candidate for cancer chemotherapy. PD98059 inhibits cell growth and proliferation in acute myelogenous leukemia (AML) cell lines; causes G1 arrest by blocking p53-dependent p21 induction. PD98059 significantly arrests the G1 phase through up-regulation of cyclin-dependent kinase (Cdk) inhibitor, and produces morphological features of apoptosis in U937 cells, which were associated with poly(ADP-ribose)polymerase (PARP) cleavage and PLC-gamma1 degradation. PD98059 also decreased the Cdk-2, Cdk-4, cyclin D1, and cyclin E expression, and increased high levels of the mitotic inhibitors p16(INIa), p21(Waf1), and p27(Kip1). Also, Bcl-2's overexpression and a caspase-3 inhibitor z-DEVD-fmk significantly attenuated PD98059-induced apoptosis through the down-regulation of caspase-3 activity, but did not attenuate G1 phase arrest. Moreover, PD98059 down-regulated Akt phosphorylation and produced a synergy effect of apoptosis with LY294002 co-treatment. Other studies have shown that the expression of KAT2B protein in cells is significantly decreased after PD98059 inhibits ERK signaling pathway, suggesting that 17β-E 2 can increase KAT2B protein expression by activating ERK signaling pathway, thus enhancing ER activity and enhancing positive feedback of estrogen effect.

Product Citations

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  J Nanobiotechnology. 2022 Feb 2;20(1):65.

  Dental pulp stem cell-derived exosomes suppress M1 macrophage polarization through the ROS-MAPK-NFκB P65 signaling pathway after spinal cord injury
  PD98059 purchased from AbMole

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  World J Gastroenterol. 2020 Jun 7;26(21):2810-2820.

  Gan Shen Fu Fang ameliorates liver fibrosis in vitro and in vivo by inhibiting the inflammatory response and extracellular signal-regulated kinase phosphorylation
  PD98059 purchased from AbMole

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  Environ Toxicol. 2020 Jun;35(6):673-682.

  Pomegranate Extract Inhibits Migration and Invasion of Oral Cancer Cells by Downregulating Matrix metalloproteinase-2/9 and Epithelial-Mesenchymal Transition
  PD98059 purchased from AbMole

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  Exp Cell Res. 2020 Jan 1;386(1):111719.

  Tim-3 suppresses the killing effect of Vγ9Vδ2 T cells on colon cancer cells by reducing perforin and granzyme B expression.
  PD98059 purchased from AbMole

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  Exp Eye Res. 2018 Nov;176:10-19.

  Rapamycin mediates mTOR signaling in reactive astrocytes and reduces retinal ganglion cell loss.
  PD98059 purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Experimental Eye Research (2018). Figure 3. PD98059 (Abmole Bioscience, Houston, TX, USA)
	Method	Western blot
	Cell Lines	ONH astrocytes
	Concentrations	25 μM
	Incubation Time	1 h
	Results	PD98059 did not significantly reduce the level of p-S6 kinase phosphorylation, but LY294002 showed a robust blockade of its phosphorylation.

	Source	PLoS One (2015). Figure 3. PD98059
	Method	Western blot
	Cell Lines	The rats
	Concentrations	2.5 mcg/5 mcl
	Incubation Time	16 h
	Results	The increased level of ERK1/2 (44/42kDa) in CCI-exposed rats was not observed in group which received repeated administration PD98059

Protocol (for reference only)

Cell Experiment
Cell lines	C-33 and C-81 cells
Preparation method	Treatment with chemotherapeutic agents. Cells were seeded in 6-well culture plates in regular culture medium at a density of 2.5*105 and 1*105 cells/well for C-33 and C-81 cells, respectively, for 2 days and then fed with SR medium, i.e., PR-free RPMI-1640 medium containing 5% heat-inactivated CS-FBS, 1% glutamine and 0.5% gentamicin. Two days after steroid starvation, one set of attached cells was harvested and counted as day 0. The remaining cells were fed with fresh SR medium and treated with PD98059, U0126, vinorelbine, docetaxel or various combinations in which the dosage of each reagent was specified. Control cells were maintained in SR medium and received solvent alone without chemotherapeutic agents. Fresh SR medium with or without chemotherapeutic agents was added every 3 days. Treatment was continued for 3 or 6 days, as described in each figure legend. To quantify the inhibition of cell growth, attached cells were trypsinized and the cells counted with a Coulter counter. The number of cells in control sets that received solvent alone was designated as 100% for comparison. All experiments were done in triplicate and repeated at least twice.
Concentrations	0~10 μM
Incubation time	3 or 6 days

Animal Experiment
Animal models	acute lung injury in mice
Formulation	DMSO, then diluted with saline
Dosages	10mg/kg
Administration	i. p.

Chemical Information

Molecular Weight	267.28
Formula	C16H13NO3
CAS Number	167869-21-8
Solubility (25°C)	DMSO 15 mg/mL
Storage	-20°C, dry, sealed, protect from light

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Di Paola R, et al. Int J Immunopathol Pharmacol. Effect of PD98059, a selective MAPK3/MAPK1 inhibitor, on acute lung injury in mice.

[2] Dokladda K, et al. FEBS Lett. PD98059 and U0126 activate AMP-activated protein kinase by increasing the cellular AMP:ATP ratio and not via inhibition of the MAP kinase pathway.

[3] Zelivianski S, et al. Int J Cancer. ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cells.

[4] Hur E, et al. Mol Pharmacol. Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1alpha.