UCN-01, 7-hydroxyl-staurosporine, inhibits kinase activity of cyclin-dependent kinases and reduces the phosphorylation of the retinoblastoma susceptibility gene product in A549 human lung cancer cell line.
UCN-01 (7-hydroxyl-staurosporine), which was initially developed as a selective protein kinase C inhibitor, has an anti-tumor effect on several human cancer cell lines in vivo. In this study, we examined whether this compound has an inhibitory effect on cell cyclin-dependent kinases (cdks) in vitro and in vivo using A549 human lung adenocarcinoma cell line. UCN-01 inhibited the retinoblastoma susceptibility gene product (pRB) kinase activity of three types of cdks (cdk 2, 4 and 6) with 50% inhibitory concentration values of 42, 32, and 58 nM, respectively, in vitro. Moreover, the amount of phosphorylated pRB was reduced by UCN-01 at a concentration of 100 nM in the living cells. Flow cytometric analysis showed that UCN-01 inhibited cell cycle progression at G1 to S transition in A549 cells at the concentration of 100 nM. These results suggest that inhibition of pRB phosphorylation by UCN-01 might lead to inhibition of the cell cycle and thereby contribute to antitumor activity of this compound.
Kawakami
K
K
Growth Factor Divison, National Cancer Center Research Institute, Tokyo, Japan.
Futami
H
H
Takahara
J
J
Yamaguchi
K
K
D000470:Alkaloids / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016160:Retinoblastoma Protein / Q000378:metabolism*; D019311:Staurosporine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D006657:Histones; D016160:Retinoblastoma Protein; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases; D019311:Staurosporine