Antitumor action of the PKC activator gnidimacrin through cdk2 inhibition.
Daphnane-type diterpene gnidimacrin (NSC252940), isolated from a Chinese plant, exhibited antitumor activity against murine leukemias and solid tumors. At concentrations of 10(-9) to 10(-10) M, this agent strongly inhibited the growth of human tumor cell lines. In sensitive human leukemia K562 cells, gnidimacrin is a PKC activator that arrests the cell cycle in the G(1) phase by inhibiting cdk2 activity. A 4 hr exposure of K562 cells to gnidimacrin induced the CDK inhibitor p21(WAF1/Cip1), but this effect was transient and did not correlate temporally with the onset of G(1) arrest. Expression of cdc25A, a phosphatase that activates cdk2, was reduced during 24-hr exposure to gnidimacrin. Moreover, the suppression corresponded in a concentration- and time-dependent manner to both the inhibition of cdk2 activity and the mobility shift observed when cdk2 was electrophoresed on SDS-PAGE, indicating that the phosphorylation state of cdk2 must change. Cyclin E, the other regulator of cdk2 activity, was not influenced by gnidimacrin. These results suggest that gnidimacrin exerts antitumor activity through suppression of cdc25A and inhibition of cdk2 activity.
Yoshida
M
M
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan. myoshida@gan2.res.ncc.go.jp
Feng
W
W
Nishio
K
K
Takahashi
M
M
Heike
Y
Y
Saijo
N
N
Wakasugi
H
H
Ikekawa
T
T
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle; D004396:Coloring Agents / Q000494:pharmacology; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D010766:Phosphorylation; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D004396:Coloring Agents; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004224:Diterpenes; D013778:Tetrazolium Salts; D013844:Thiazoles; C013006:gnidimacrin; D011494:Protein Kinases; C102333:histone H1 kinase; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases; C022616:thiazolyl blue