Effect of suramin on p34cdc2 kinase in vitro and in extracts from human H69 cells: evidence for a double mechanism of action.
We examined the effect of suramin, an anticancer agent and a functional analog of naturally occuring glycosaminoglycans, on p34cdc2 kinase. We find that suramin strongly inhibits the catalytic activity of purified p34cdc2 kinase (IC50 approximately 4 microM), whereas it only weakly inhibits the p13-agarose precipitated kinase activity from nuclear and cytoplasmic extracts of the asynchronous H69 human small cell lung cancer cells. We also find that the tyrosine phosphorylation of p34cdc2 kinase in the nuclear extract is increased about twice when the extracts are preincubated with 50 microM of suramin prior to the p13-agarose precipitation. We propose that this increase might result from the inhibitory effect of suramin towards p34cdc2-specific tyrosine phosphatases. These results suggest both a direct and an indirect effect of suramin on p34cdc2 kinase. We also find that heparin is a potent inhibitor of purified cdc2 kinase (IC50 approximately 3.5 micrograms/ml). Therefore, glycosaminoglycans might be physiological regulators of p34cdc2 kinase in vivo.
Bojanowski
K
K
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Nishio
K
K
Fukuda
M
M
Larsen
A K
AK
Saijo
N
N
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000302:isolation & purification / Q000378:metabolism*; D018288:Carcinoma, Small Cell; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D002846:Chromatography, Affinity; D003593:Cytoplasm / Q000201:enzymology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D013498:Suramin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D013498:Suramin; D006493:Heparin; D016203:CDC2 Protein Kinase