Carpe low-dose aspirin: the new anti-cancer face of an old anti-platelet drug

Cancer metastasis is a dynamic process during which cancer cells separate from a primary tumor, migrate through the vessel wall into the bloodstream, and extravasate at distant sites to form secondary colonies. During this process, circulating tumor cells are subjected to shear stress forces from blood flow, and in contact with plasma proteins and blood cells of the immune and hemostatic system, including platelets. Many studies have shown an association between high platelet count and cancer metastasis, suggesting that platelets may play an occult role in tumorigenesis. This mini-review summarizes recent and emerging discoveries of mechanisms by which cancer cells activate platelets and the role of activated platelets in promoting tumor growth and metastasis. Moreover, the review discusses how aspirin has the potential for being clinically used as an adjuvant in cancer therapy

Potentiation of TRAP-6-induced platelet dense granule release by blockade of P2Y₁₂ signaling with MRS2395

<p>The release of ADP from platelet dense granules and its binding to platelet P2Y₁₂ receptors is key to amplifying the initial hemostatic response and propagating thrombus formation. P2Y₁₂ has thus emerged as a therapeutic target to safely and effectively prevent secondary thrombotic events in patients with acute coronary syndrome or a history of myocardial infarction. Pharmacological inhibition of P2Y₁₂ receptors represents a useful approach to better understand the signaling mediated by these receptors and to elucidate the role of these receptors in a multitude of platelet hemostatic and thrombotic responses. The present work examined and compared the effects of four different P2Y₁₂ inhibitors (MRS2395, ticagrelor, PSB 0739, and AR-C 66096) on platelet function in a series of in vitro studies of platelet dense granule secretion and trafficking, calcium generation, and protein phosphorylation. Our results show that in platelets activated with the PAR-1 agonist TRAP-6 (thrombin receptor-activating peptide), inhibition of P2Y₁₂ with the antagonist MRS2395, but not ticagrelor, PSB 0739 or AR-C 66096, potentiated human platelet dense granule trafficking to the plasma membrane and release into the extracellular space, cytosolic Ca²⁺ influx, and phosphorylation of GSK3β-Ser9 through a PKC-dependent pathway. These results suggest that inhibition of P2Y₁₂ with MRS2395 may act in concert with PAR-1 signaling and result in the aberrant release of ADP by platelet dense granules, thus reducing or counteracting the anticipated anti-platelet efficacy of this inhibitor.</p

Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions

Human platelets express two protease-activated receptors (PARs), PAR1 (F2R) and PAR4 (F2RL3), which are activated by a number of serine proteases that are generated during pathological events and cause platelet activation. Recent interest has focused on PAR4 as a therapeutic target, given PAR4 seems to promote experimental thrombosis and procoagulant microparticle formation, without a broadly apparent role in hemostasis. However, it is not yet known whether PAR4 activity plays a role in platelet-leukocyte interactions, which are thought to contribute to both thrombosis and acute or chronic thrombo-inflammatory processes. We sought to determine whether PAR4 activity contributes to granule secretion from activated platelets and platelet-leukocyte interactions. We performed in vitro and ex vivo studies of platelet granule release and platelet-leukocyte interactions in the presence of PAR4 agonists including PAR4 activating peptide, thrombin, cathepsin G, and plasmin in combination with small-molecule PAR4 antagonists. Activation of human platelets with thrombin, cathepsin G, or plasmin potentiated platelet dense granule secretion that was specifically impaired by PAR4 inhibitors. Platelet-leukocyte interactions and platelet P-selectin exposure the following stimulation with PAR4 agonists were also impaired by activated PAR4 inhibition in either a purified system or in whole blood. These results indicate PAR4-specific promotion of platelet granule release and platelet-leukocyte aggregate formation and suggest that pharmacological control of PAR4 activity could potentially attenuate platelet granule release or platelet-leukocyte interaction-mediated pathological processes