Effects of phorbol diesters and teleocidin on normal human platelets.
Teleocidins are newly described indole alkaloid tumor promoters that are structurally distinct from phorbol diesters (PDE). We compared the effects of teleocidin and selected PDE on platelet aggregation, secretion and aspects of arachidonate metabolism. Three tumor-promoting PDE (phorbol myristate acetate (PMA), phorbol dibutyrate (PDBu) and 4-beta-phorbol didecanoate (4-beta-PDD] and a non-tumor promoting PDE (4-alpha-phorbol didecanoate (4-alpha-PDD] were used. Teleocidin and tumor promoting PDE caused platelet aggregation after a delay that was inversely related to tumor promoter concentration and also triggered secretion of alpha- and dense granules and selective release of lysosomal enzymes. Aggregation and its associated 125I-fibrinogen binding to platelets were both inhibited by Na2EDTA. 4-alpha-PDD was ineffective. Analysis of platelet aggregation responses and activation kinetics revealed that PDBu was 11.7 times less potent than teleocidin PMA, or 4-beta-PDD. Neither PDE nor teleocidin stimulated 14C-arachidonate release from normal human platelets, and both aggregated aspirin-treated platelets. These results show that representatives of two structurally distinct classes of tumor promoters, phorbol diesters and indole alkaloids, are potent activators of platelet aggregation, fibrinogen binding, and granule/lysosomal secretion, by a mechanism that bypasses arachidonate release and formation of cyclooxygenase-dependent arachidonate metabolites.
D001095:Arachidonic Acids / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008235:Lyngbya Toxins / Q000494:pharmacology*; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D001620:beta-Thromboglobulin / Q000378:metabolism
D001095:Arachidonic Acids; D008235:Lyngbya Toxins; D010703:Phorbol Esters; D001620:beta-Thromboglobulin; C022176:teleocidins; D012701:Serotonin; D005340:Fibrinogen