title: Differential inhibition of tumour cell-induced platelet aggregation by the nicotinate aspirin prodrug (ST0702) and aspirin.
abstract: OBJECTIVE
  Tumour cell-induced platelet aggregation (TCIPA) facilitates cancer cell invasion, angiogenesis and the formation of metastatic foci. TCIPA can be modulated by pharmacological inhibitors of MMP-2 and ADP; however, the COX inhibitor aspirin did not prevent TCIPA. In this study, we have tested the pharmacological effects of a new group of isosorbide-based aspirin prodrugs on TCIPA.
  
  
  METHODS
  TCIPA was induced in human platelets by mixing with human adenocarcinoma or fibrosarcoma cells under no flow and flow conditions. The release of gelatinases and P-selectin expression during TCIPA were studied by zymography and flow cytometry respectively.
  
  
  RESULTS
  Tumour cells caused platelet aggregation. This aggregation resulted in the release of MMP-2 and a significant up-regulation of P-selectin on platelets, indicative of platelet activation. Pharmacological modulation of TCIPA revealed that ST0702, one of the aspirin prodrugs, down-regulated TCIPA while aspirin was ineffective. The deacetylated metabolite of ST0702, 5-nicotinate salicylate (ST0702 salicylate), down-regulated both ADP-stimulated platelet aggregation and TCIPA.
  
  
  CONCLUSIONS
  Our results show that ST0702 was an effective inhibitor of TCIPA in vitro. Its deacetylated metabolite may contribute to the effects of ST0702 by inhibiting ADP-mediated TCIPA.
authors: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland. carlos.medina@tcd.ie
authors: Carlos
authors: C
authors: Medina
authors: Shona
authors: S
authors: Harmon
authors: Iwona
authors: I
authors: Inkielewicz
authors: Maria Jose
authors: MJ
authors: Santos-Martinez
authors: Michael
authors: M
authors: Jones
authors: Paula
authors: P
authors: Cantwell
authors: Despina
authors: D
authors: Bazou
authors: Mark
authors: M
authors: Ledwidge
authors: Marek W
authors: MW
authors: Radomski
authors: John F
authors: JF
authors: Gilmer
mesh_terms: D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D002450:Cell Communication / Q000187:drug effects*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005434:Flow Cytometry; D006801:Humans; D007547:Isosorbide / Q000031:analogs & derivatives* / Q000494:pharmacology; D008858:Microscopy, Phase-Contrast; D009525:Niacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D011355:Prodrugs; C573785:isosorbide-5-nicotinate-2-aspirinate; D009525:Niacin; D010830:Physostigmine; D001241:Aspirin; D007547:Isosorbide