EFFECTS OF SURAMIN-RELATED AND OTHER CLINICALLY THERAPEUTIC POLYANIONS ON PROTEIN-KINASE-C ACTIVITY

The mechanism of the antineoplastic effects of suramin may involve int erference with signal transduction, but in general is not well underst ood. We examined several polyanions to determine their effects on the kinase activity of the protein kinase C (PKC) beta(1) and other PKC is oforms. Similar to suramin, a phosphorothioate oligodeoxynucleotide 28 -mer homopolymer of cytidine (SdC28) inhibited the phosphatidylserine and Ca2+-dependent phosphorylation of an epidermal growth factor recep tor octapeptide substrate, The inhibition by suramin was mixed competi tive/noncompetitive with respect to ATP, but uncompetitive with respec t to substrate. In contrast, the inhibition by SdC28 was competitive w ith respect to substrate (K-i = 5.4 mu M) and not competitive with res pect to ATP. The PKC alpha and beta(1) isoforms were inhibited to the same extent with SdC28, while PKC epsilon was not inhibited, SdC28, in the absence of lipid cofactor, stimulated substrate phosphorylation, and in the absence of substrate induced PKC beta(1) autophosphorylatio n, Similar behavior was seen with another polyanion, the polysulfated carbohydrate pentosan polysulfate (polyxylyl hydrogen sulfate), H4, a bis-naphthalene disulfonate tetraanion structurally related to suramin , also inhibited kinase activity but was not competitive with respect to ATP, Dianions closely related to H4 failed to inhibit PKC beta(1), suggesting that multiple (>2) negative charges are required, The inter actions of polyanions with PKC are complex, and are dependent on the m olecular structure of the polyanion, the presence of cofactors, and th e PKC isoform.