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

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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.

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

Fingerprint

cdc25 Phosphatases
Dual-Specificity Phosphatases
Cell Cycle Checkpoints
G1 Phase
Antineoplastic Agents
Cell Line
Camptothecin
Retinoblastoma Protein
Cyclin-Dependent Kinases
cinnamic acid
TPY-835
G2 Phase
Growth
Phosphoric Monoester Hydrolases
Fluorouracil
Cell Division
Cisplatin
Inhibitory Concentration 50
Libraries
Lung Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Aoyagi, Y., Masuko, N., Ohkubo, S., Kitade, M., Nagai, K., Okazaki, S., ... 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

A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity. / Aoyagi, Yoshimi; Masuko, Norio; Ohkubo, Shuichi; Kitade, Makoto; Nagai, Kentaro; Okazaki, Shinji; Wierzba, Konstanty; Terada, Tadafumi; Sugimoto, Yoshikazu; Yamada, Yuji.

In: Cancer Science, Vol. 96, No. 9, 09.2005, p. 614-619.

Research output: Contribution to journalArticle

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, vol. 96, no. 9, pp. 614-619. https://doi.org/10.1111/j.1349-7006.2005.00086.x
Aoyagi, Yoshimi ; Masuko, Norio ; Ohkubo, Shuichi ; Kitade, Makoto ; Nagai, Kentaro ; Okazaki, Shinji ; Wierzba, Konstanty ; Terada, Tadafumi ; Sugimoto, Yoshikazu ; Yamada, Yuji. / A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity. In: Cancer Science. 2005 ; Vol. 96, No. 9. pp. 614-619.
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