A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity
Authors: Aoyagi, Yoshimi; Masuko, Norio1; Ohkubo, Shuichi1; Kitade, Makoto1; Nagai, Kentaro1; Okazaki, Shinji1; Wierzba, Konstanty1; Terada, Tadafumi1; Sugimoto, Yoshikazu1; Yamada, Yuji1
Source: Cancer Science, Volume 96, Number 9, September 2005 , pp. 614-619(6)
Publisher: Blackwell Publishing
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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. (Cancer Sci 2005; 96: 614–619)Document Type: Research article
DOI: 10.1111/j.1349-7006.2005.00086.x
Affiliations: 1: Cancer Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Company, 1-27 Misugidai, Hanno-shi, Saitama 357-8527, Japan
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