INTRODUCTION: PD98059, having the structural formula [2-(2â€-amino-3â€-methoxyphenyl)-oxanaphthalen-4-one] is a potent and flavonoid inhibitor of MEK (mitogen-activated protein kinase). PD98059 in a concentration of less than or equal to 20 uM does not produce cytotoxicity in the cultures of the human breast epithelial lines of cells, i.e. MCF10A. The molecule works weakly as cystostatic at the concentration of less than or equal to 10 uM. PD98059 †SIGNIFICANT CONCENTRATIONS: In an experiment, the exposure of PD98059 inside the cultures with the concentration of less than or equal to 20 uM did not produce any remarkable impacts up to 2 to 22 hours. At such concentration, there were no overall extracellular signal-regulated kinase contents. Nevertheless, when the cultures were exposed to PD98059, rapid loss up to 95% related to the dual phosphorylation forms of extracellular kinases was resulted. These results were obtained at the concentration of greater or equal to 1 uM (IC50). INDUCTION OF APOPTOSIS: The impacts of PD98059 have been evaluated in various study models, comprising of different cell types. This molecule has been emerged as the inhibitor which can induce the apoptosis and the GI cell cycle arrest by means of up-regulation of the cyclin dependent kinase inhibitor p27 kip1 [1, 2]. In addition to that, PD98059 can produce the synergistic effect of apoptosis when it is employed along with different other chemotherapeutic molecules [3, 4]. PD98059 AND BCL-2 FAMILY: The cell and the mitochondrial physiology can be regulated by the members of Bcl-2 family belonging to the anti-apoptotic proteins [5]. According to the previous research studies, Bcl-2 over-expression takes part in the resistance development of various cancer cells against the molecules that are given for the eradication of cancer [6, 7]. According to a research study, PD98059 can develop apoptosis in HeLa cells by means of down regulation of Bcl-2 at the protein level. Nevertheless, the actual biochemical mechanisms via which this molecule impacts on Bcl-2 over-expression of cells is still uncertain [8]. MECHANISM OF APOPTOSIS: PD98059 brings a significant G1 phase arrest via up-regulation of the Cdk inhibitors, like INI4a, p21Wafl/ Cip1, p27 Kip 1, etc. in different human leukemic cells (U937). It has been observed that Bcl-2 over-expression develops as a result of remarkable decrease in the apoptosis, induced or developed by PD98059. These effects are developed as a result of caspase-3 inhibition activity and not due to the modulation of G1 phase arrest. PD98059 †ANALYSIS OF MECHANISMS AND ACTIONS: The analysis by means of flow cytometry clearly reveals the role of PD98059 in arresting cells in the G1 phase via up-regulation of Cdk inhibition, p16 INI4a, p21 Waf1/Cip1 and p27 Kip1, etc. in addition to that, it has been observed that PD98059 in its highest concentration, i.e. 60 uM can induce the intermediate level apoptosis in U937 cells. Bcl-2 over-expression and the caspase-3 inhibition is enough to suppress the apoptosis induced by PD98059. Nevertheless, the remarkable apoptotic death can be resulted due to the PD98059 induced inhibition of Akt pathway and the co-inhibition of Akt pathway and ERK. CONCLUSION: In conclusion, PD98059 is a specific inhibitor for ERK1/2, and it can efficiently suppress the Bcl-2 as well as activates the caspase-3. In addition to that, it can work in combination with Akt signaling pathway in the response of apoptotic stimuli. REFERENCES: 1. Yamaguchi K, Tomita H, Sugano E, Nakazawa T, Tamai M. Mitogen-activated protein kinase inhibitor, PD98059, inhibits rat retinal pigment epithelial cell replication by cell cycle arrest. Jpn J Ophthalmol 2002;46:634â€9. 2. Hoshino R, Tanimura S, Watanabe K, Kataoka T, Kohno M. Blockade of the extracellular signal-regulated kinase pathway induces marked G1 cell cycle arrest and apoptosis in tumor cells in which the pathway is constitutively activated: up-regulation of p27(Kip1). J Biol Chem 2001;276:2686â€92. 3. Poruchynsky MS, Giannakakou P, Ward Y, Bulinski JC, Telford WG, Robey RW, et al. Accompanying protein alterations in malignant cells with a microtubule-polymerizing drug-resistance phenotype and a primary resistance mechanism. Biochem Pharmacol 2001;62:1469â€80. 4. Yu C, Krystal G, Varticovksi L, McKinstry R, Rahmani M, Dent P, et al. Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Cancer Res 2002;62:188â€99. 5. Murphy E, Imahashi K, Steenbergen C. Bcl-2 regulation of mitochondrial energetics. Trends Cardiovasc Med 2005;15:283â€90. 6. Park JW, Choi YJ, Suh SI, Baek WK, Suh MH, Jin IN, et al. Bcl-2 overexpression attenuates resveratrol-induced apoptosis in U937 cells by inhibition of caspase-3 activity. Carcinogenesis 2001;22:1633â€9. 7. Woo KJ, Yoo YH, Park JW, Kwon TK. Bcl-2 attenuates anticancer agents-induced apoptosis by sustained activation of Akt/protein kinase B in U937 cells. Apoptosis 2005;10:1333â€43. 8. Lee MW, Bach JH, Lee HJ, Lee DY, Joo WS, Kim YS, et al. The activation of ERK1/2 via a tyrosine kinase pathway attenuates trailinduced apoptosis in HeLa cells. Cancer Investig 2005;23:586â€92.
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