title: Suramin inhibits the phosphorylation and catalytic activity of DNA topoisomerase II in human lung cancer cells.
abstract: Suramin is a prototype of a new class of anticancer drugs. We investigated the action of suramin on the signal transduction pathways to DNA topoisomerase II (Topo II). Suramin showed a growth-inhibitory effect on a human lung cancer cell line (PC-9) with an IC50 of about 160 micrograms/ml. Suramin inhibited the catalytic activity of Topo II with an IC50 of about 100 micrograms/ml without stabilization of the cleavable complex of DNA and Topo II. Suramin decreased the phosphorylation of Topo II with an IC50 of 175 micrograms/ml, but did not change the degree of Topo II expression. These IC50 values for inhibition of catalytic activity and phosphorylation of Topo II were equivalent to the growth-inhibitory dose determined by tetrazolium dye assay. Phosphorylation of the tyrosine residues of Topo II was not changed by suramin. In the presence of okadaic acid, a potent inhibitor of serine/threonine protein phosphatase, suramin also decreased the phosphorylation of Topo II, suggesting that the drug did not act on the serine/threonine protein phosphatases inhibited by okadaic acid. Suramin also inhibited the protein kinase C (PKC) activity of PC-9 cells. These results suggest that suramin decreases the phosphorylation of Topo II mediated by PKC. This effect of suramin might cause the inhibition of Topo II activity resulting in the growth inhibition of tumor cells.
authors.affiliation: Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Funayama
authors.forename: K
authors.initials: K
authors.lastname: Nishio
authors.forename: Y
authors.initials: Y
authors.lastname: Takeda
authors.forename: N
authors.initials: N
authors.lastname: Kubota
authors.forename: T
authors.initials: T
authors.lastname: Ohira
authors.forename: T
authors.initials: T
authors.lastname: Ohmori
authors.forename: S
authors.initials: S
authors.lastname: Ohta
authors.forename: H
authors.initials: H
authors.lastname: Ogasawara
authors.forename: S
authors.initials: S
authors.lastname: Hasegawa
authors.forename: N
authors.initials: N
authors.lastname: Saijo
mesh_terms: D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D018288:Carcinoma, Small Cell / Q000201:enzymology*; D002460:Cell Line; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000302:isolation & purification / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004988:Ethers, Cyclic / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000201:enzymology*; D008970:Molecular Weight; D019319:Okadaic Acid; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D013498:Suramin / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D004988:Ethers, Cyclic; D059005:Topoisomerase II Inhibitors; D019319:Okadaic Acid; D013498:Suramin; D017027:Protein Tyrosine Phosphatases; D004250:DNA Topoisomerases, Type II