A novel MEK1/2 inhibitor induces G1/S cell cycle arrest in human fibrosarcoma cells.

Abstract

Blockade of the ERK pathway has antitumor effects against malignant tumor cells. In this study, we investigated the antitumor activity of JTP-70902, a novel specific MEK inhibitor, against human fibrosarcoma cells in which the ERK pathway is constitutively activated. JTP-70902 was synthesized at Japan Tabacco. Human fibrosarcoma HT1080 cells were cultured. JTP-70902 was added at various concentrations. The number of viable cells was counted employing a trypan blue dye exclusion test. Unsynchronized cells were exposed to JTP-70902 for 24 h. The nuclei were stained with propidium iodide. The DNA content was measured using a FACSCalibur flow cytometer. Protein extraction and Western blot analysis were performed. (1) A dose-dependent inhibition of cell growth was observed at concentrations of 10 nM or more. Forty-eight hours after the treatment, the growth of HT1080 cells was completely inhibited by 200 nM JTP-70902. (2) FACS analysis revealed that a 24-h exposure to JTP-70902 increased the population of G1/S phase cells in a dose-dependent manner. (3) The phosphorylation of ERK was inhibited by JTP-70902. Furthermore, after the treatment with JTP-70902, p21WAF1/CIP1 and p27KIP1 protein expression increased and the phosphorylation of RB was reduced. Our results showed that JTP-70902 inhibits cell growth and induces cell cycle arrest in human Ras mutant fibrosarcoma cells. These results indicate that JTP-70902 might be an attractive compound for molecular-targeting chemotherapy for malignant soft tissue tumors with the activation of the Ras-MEK-ERK pathway.

• Authors: Taka-Aki Matsui, Hiroaki Murata, Yoshihiro Sowa, Tomoya Sakabe, Kazutaka Koto, Naoyuki Horie, Yoshiro Tsuji, Toshiyuki Sakai, Toshikazu Kubo
• Journal: Oncology reports (Oncol Rep) Vol. 24 Issue 2 Pg. 329-33 (Aug 2010) ISSN: 1791-2431 [Electronic] Greece
• PMID: 20596617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Protein Kinase Inhibitors
• Pyrimidinones
• Sulfonamides
• Cyclin-Dependent Kinase Inhibitor p27
• MAP2K2 protein, human
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• N-(3-(5-(4-bromo-2-fluorophenylamino)-3-cyclopropyl-8-methyl-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido(2,3-d)pyrimidin-1-yl)phenyl)methanesulfonamide

Topics

• Antineoplastic Agents (pharmacology)
• Cell Cycle (drug effects, physiology)
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Drug Evaluation, Preclinical
• Fibrosarcoma (pathology)
• G1 Phase (drug effects)
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidinones (pharmacology)
• S Phase (drug effects)
• Sulfonamides (pharmacology)
• Time Factors
• Tumor Cells, Cultured