Synonym: PD 98059
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.
|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.
|Incubation time||3 or 6 days|
|Animal models||acute lung injury in mice|
|Formulation||DMSO, then diluted with saline|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥25 mg/mL|
Effect of PD98059, a selective MAPK3/MAPK1 inhibitor, on acute lung injury in mice.
Di Paola R, et al. Int J Immunopathol Pharmacol. 2009 Oct-Dec;22(4):937-50. PMID: 20074457.
PD98059 and U0126 activate AMP-activated protein kinase by increasing the cellular AMP:ATP ratio and not via inhibition of the MAP kinase pathway.
Dokladda K, et al. FEBS Lett. 2005 Jan 3;579(1):236-40. PMID: 15620719.
ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cells.
Zelivianski S, et al. Int J Cancer. 2003 Nov 10;107(3):478-85. PMID: 14506750.
Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1alpha.
Hur E, et al. Mol Pharmacol. 2001 May;59(5):1216-24. PMID: 11306706.
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