Pharmacological assessment of ibuprofen arginate on platelet aggregation and colon cancer cell killing.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, are amongst the most commonly used medications and produce their anti-inflammatory and analgesic benefits by blocking cyclooxygenase (COX)-2. These drugs also have the potential to prevent and treat cancer and some members of the class including ibuprofen can produce anti-platelet effects. Despite their utility, all NSAIDs are associated with increased risk of cardiovascular side effects which our recent work suggests could be mediated by increased levels of the endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) leading to reduced endothelial NOS activity and associated endothelial cell dysfunction. ADMA is a cardiotoxic hormone and biomarker of cardiovascular risk whose effects can be prevented by l-arginine. The ibuprofen salt, ibuprofen arginate (Spididol®) was created to increase drug solubility but we have previously established that it not only effectively blocks COX-2 but also provides an arginine source able to reverse the effects of ADMA in vitro and in vivo. Here we have gone on to explore whether the formulation of ibuprofen with arginine influences the potency and efficacy of the parent molecule using a range of simple in vitro assays designed to test the effects of NSAIDs on (i) platelet aggregation and (iii) colon cancer cell killing. Our findings demonstrate that ibuprofen arginate retains these key functional effects of NSAIDs with similar or increased potency compared to ibuprofen sodium, further illustrating the potential of ibuprofen arginate as an efficacious drug with the possibility of improved cardiovascular safety.
National Heart & Lung Institute, Imperial College London, London, United Kingdom. Electronic address: b.ahmetaj@imperial.ac.uk.
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Ahmetaj-Shala
National Heart & Lung Institute, Imperial College London, London, United Kingdom.
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Tesfai
National Heart & Lung Institute, Imperial College London, London, United Kingdom.
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Constantinou
National Heart & Lung Institute, Imperial College London, London, United Kingdom.
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Leszczynski
Translational Medicine & Therapeutics, Queen Mary University of London, London, United Kingdom.
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Chan
National Heart & Lung Institute, Imperial College London, London, United Kingdom.
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Gashaw
National Heart & Lung Institute, Imperial College London, London, United Kingdom.
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Galaris
National Heart & Lung Institute, Imperial College London, London, United Kingdom.
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Mazi
Translational Medicine & Therapeutics, Queen Mary University of London, London, United Kingdom.
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Warner
National Heart & Lung Institute, Imperial College London, London, United Kingdom. Electronic address: n.kirkby@imperial.ac.uk.
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Kirkby
National Heart & Lung Institute, Imperial College London, London, United Kingdom. Electronic address: j.a.mitchell@ic.ac.uk.
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Mitchell
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000008:administration & dosage*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D004338:Drug Combinations; D010975:Platelet Aggregation Inhibitors; D001120:Arginine; D007052:Ibuprofen; C106674:ibuprofen arginine
Cancer; Cyclooxygenase; Ibuprofen; Nitric oxide; Platelets; l-arginine