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Review
. 2017 Jun;36(2):289-303.
doi: 10.1007/s10555-017-9675-z.

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention

Argentina Ornelas  1 , Niki Zacharias-Millward  1 , David G Menter  2 , Jennifer S Davis  3 , Lenard Lichtenberger  4 , David Hawke  5 , Ernest Hawk  6 , Eduardo Vilar  6 , Pratip Bhattacharya  1 , Steven Millward  7
Affiliations
Review

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention

Argentina Ornelas et al. Cancer Metastasis Rev. 2017 Jun.

Abstract

After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin's chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism.

Keywords: Acetylome; Aspirin; Chemoprevention; Cyclooxygenase-1; Cyclooxygenase-2; Platelets.

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Figures

Fig. 1
Fig. 1
The Chemistry of Aspirin Under Basic Conditions. Deprotonation of the carboxylic acid results in the formation of the aspirin anion which abstracts a proton from water to generate a nucleophilic hydroxide anion. The negatively charged hydroxide attacks the carbonyl carbon of the acetate group resulting in hydrolysis of aspirin into salicylate and acetate (general base catalysis) [15, 16]. Recent work also suggests that a mixed anhydride can be formed under basic conditions through a hemiorthoester anion intermediate [18] although the contribution of this intermediate to the mechanism of hydrolysis is unknown
Fig. 2
Fig. 2
Reactivity of aspirin in different biological environments of proteins
Fig. 3
Fig. 3
Platelet Activation. Platelet activation is initiated by multiple stimuli including thrombin, ADP, and fibrinogen. This results in the initiation of prostaglandin synthesis by COX-1 which is directly inhibited by aspirin. Aspirin can also modulate the clotting response by acetylating other serum proteins, most notably fibrinogen
See this image and copyright information in PMC

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