A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity.
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 microM, 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.
Aoyagi
Yoshimi
Y
Cancer Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Company, 1-27 Misugidai, Hanno-shi, Saitama 357-8527, Japan. aoyagiyo@taiho.co.jp
Masuko
Norio
N
Ohkubo
Shuichi
S
Kitade
Makoto
M
Nagai
Kentaro
K
Okazaki
Shinji
S
Wierzba
Konstanty
K
Terada
Tadafumi
T
Sugimoto
Yoshikazu
Y
Yamada
Yuji
Y
D018797:Cell Cycle Proteins / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019008:Drug Resistance, Neoplasm; D016193:G1 Phase / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011720:Pyrazoles; D016160:Retinoblastoma Protein; C504880:TPY-835; D020687:cdc25 Phosphatases