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Differential inhibition of tumour cell‐induced platelet aggregation by the nicotinate aspirin prodrug (ST0702) and aspirin
Author(s) -
Medina Carlos,
Harmon Shona,
Inkielewicz Iwona,
SantosMartinez Maria Jose,
Jones Michael,
Cantwell Paula,
Bazou Despina,
Ledwidge Mark,
Radomski Marek W.,
Gilmer John F.
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01794.x
Subject(s) - prodrug , aspirin , pharmacology , chemistry , platelet , metabolite , platelet activation , flow cytometry , biochemistry , medicine , immunology
BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.