A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity

Yoshimi Aoyagi, Norio Masuko, Shuichi Ohkubo, Makoto Kitade, Kentaro Nagai, Shinji Okazaki, Konstanty Wierzba, Tadafumi Terada, Yoshikazu Sugimoto, Yuji Yamada

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The Cdc25 dual-specificity phosphatases are key regulators of cell cycle progression through activation of cyclin-dependent kinases (Cdk). Three homologs exist in humans: Cdc25A, Cdc25B, and Cdc25C. Cdc25A and Cdc25B have oncogenic properties and are overexpressed in some types of tumors. Compounds that inhibit Cdc25 dual-specificity phosphatase activity might thus be potent anticancer agents. We screened several hundred compounds in a library using an in vitro phosphatase assay, with colorimetric measurement of the conversion of p-nitrophenyl phosphate (pNPP) to p-nitrophenol by the catalytic domain of recombinant human Cdc25, and discovered TPY-835, which inhibits Cdc25A and Cdc25B activity (IC50 = 5.1 and 5.7 μM, respectively). TPY-835 had mixed inhibition kinetics for Cdc25A and Cdc25B. TPY-835 caused cell cycle arrest in the G1 phase in human lung cancer cells (A549 and SBC-5) but not cell cycle arrest in the G2/M phase. After treatment with TPY-835, the activation of Cdk2 was suppressed and phosphorylation of the retinoblastoma (Rb) protein was decreased in SBC-5 cells. In addition, TPY-835 induced an increase of the sub-G1 phase cell population after 48-72 h treatment. The growth inhibitory effects of TPY-835 against cisplatin (CDDP)-, camptothecin- and 5-FU-resistant cell lines are comparable to the growth inhibitory effect on their parental lines, thus indicating that TPY-835 did not show cross-resistance to these cell lines. These results suggest that TPY-835 is a promising candidate for constructing a novel class of antitumor agents that can control the cell cycle progression of cancer cells.

Original languageEnglish
Pages (from-to)614-619
Number of pages6
JournalCancer science
Volume96
Issue number9
DOIs
Publication statusPublished - 2005 Sep

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Aoyagi, Y., Masuko, N., Ohkubo, S., Kitade, M., Nagai, K., Okazaki, S., Wierzba, K., Terada, T., Sugimoto, Y., & Yamada, Y. (2005). A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity. Cancer science, 96(9), 614-619. https://doi.org/10.1111/j.1349-7006.2005.00086.x