A novel MEK1/2 inhibitor induces G(1)/S cell cycle arrest in human fibrosarcoma cells

作者：Matsui Taka Aki; Murata Hiroaki^*; Sowa Yoshihiro; Sakabe Tomoya; Koto Kazutaka; Horie Naoyuki; Tsuji Yoshiro; Sakai Toshiyuki; Kubo Toshikazu

来源：Oncology Reports, 2010, 24(2): 329-333.

DOI：10.3892/or_00000863

• fibrosarcoma
• MEK inhibitor
• p21(WAFI/CIPI)
• p27(KIPI)
• cell cycle arrest

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 JTP70902. (2) FACS analysis revealed that a 24-h exposure to JTP-70902 increased the population of G(1)/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, p21(WAFI/CIPI) and p27(KIPI) protein expression increased and the phosphorylation of RB was redued. 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.

• 出版日期2010-8