Inhibition of platelet activation by tyrosine kinase inhibitors

Rendu, Francine; Eldor, Amiram; Grelac, Françoise; Bachelot, C; Gazit, Aviv; Gilon, Chaim; Lévy-Toledano, S; Levitzki, Alexander

doi:10.1016/0006-2952(92)90119-4

Cited by 56 publications

(30 citation statements)

References 27 publications

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“…As noted in previous reports (Rendu et al, 1992;Ozaki et al, 1993) and in this study, although tyrosine kinase inhibitors, including genistein, PP1, and piceatannol, are effective in inhibiting collagen-induced platelet aggregation (IC 50 of 13.7 Ϯ 0.6, 2.1 Ϯ 0.4, and 17.2 Ϯ 2.3 M, respectively; n ϭ 3), they are much less effective in inhibiting platelet aggregation caused by thrombin (IC 50 Ͼ 200 M). In contrast, although MNS had distinct effect on Ca 2ϩ signaling triggered by thrombin and collagen, it inhibited platelet aggregations by these two stimulators in a similar range of concentration.…”

Section: Mns Inhibits Platelet Gpiib/iiia Activation 1387supporting

confidence: 72%

“…Upon stimulation of platelets with agonists, there is a dramatic increase in the levels of phosphotyrosine of multiple platelet proteins. A role for protein tyrosine phosphorylation in inside-out GPIIb/IIIa signaling is suggested by the observation that tyrosine kinase inhibitors decrease GPIIb/IIIa activation and platelet aggregation (Asahi et al, 1992;Rendu et al, 1992;Furman et al, 1994). Furthermore, Syk null murine platelets have been shown to cause a reduction in fibrinogen binding in response to ADP and epinephrine (Law et al, 1999).…”

Section: Mns Inhibits Platelet Gpiib/iiia Activation 1387mentioning

confidence: 99%

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Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

Wang

Wu²,

2006

Mol Pharmacol

112

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Binding fibrinogen to activated glycoprotein (GP)IIb/IIIa is the final common pathway of platelet aggregation and has become a successful target for antiplatelet therapy. In the present study, we found that a small chemical compound, 3,4-methylenedioxy-␤-nitrostyrene (MNS), exhibited potent and broadspectrum inhibitory effects on human platelet aggregation caused by various stimulators. Moreover, addition of MNS to human platelets that had been aggregated by ADP caused a rapid disaggregation. We demonstrated that the antiaggregatory activity of MNS is due to inhibition of GPIIb/IIIa activation by measuring the binding amount of PAC-1 in platelets. In contrast, MNS is not a direct antagonist of GPIIb/IIIa, because MNS did not affect fibrinogen binding to fixed ADP-stimulated platelets. By investigating how MNS inhibits GPIIb/IIIa activation, we found that MNS potently inhibited the activity of tyrosine kinases (Src and Syk) and prevented protein tyrosine phosphorylation and cytoskeletal association of GPIIb/IIIa and talin, but it had no direct effects on protein kinase C, Ca 2ϩ mobilization, Ca 2ϩ -dependent enzymes (myosin light chain kinase and calpain), and arachidonic acid metabolism, and it did not affect the cellular levels of cyclic nucleotides. Therefore, MNS represents a new class of tyrosine kinase inhibitor that potently prevents GPIIb/IIIa activation and platelet aggregation without directly affecting other signaling pathways required for platelet activation. Because MNS inhibits GPIIb/IIIa functions in a manner different from GPIIb/IIIa antagonists, this feature may provide a new strategy for treatment of platelet-dependent thrombosis.

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Section: Mns Inhibits Platelet Gpiib/iiia Activation 1387supporting

confidence: 72%

Section: Mns Inhibits Platelet Gpiib/iiia Activation 1387mentioning

confidence: 99%

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

Wang

Wu²,

2006

Mol Pharmacol

112

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“…32 Some studies have reported the blocking effects of tyrosine kinase inhibitors on different platelet functions. [33][34][35] However, most of the tyrosine kinase inhibitors used so far were nonselective, and it is still difficult to ascertain a role for the different tyrosine kinases present in platelet. Interestingly, the increasing development of small-molecule inhibitors of kinases, particularly in targeted cancer therapy, allow us now to test more selective compounds.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies [33][34][35] have addressed this question using nonselective tyrosine kinase inhibitors; however, it is difficult to draw clear conclusions. Very recent data suggest that selective Syk inhibitors may be of interest as antiplatelet agents to prevent thrombosis 42 or HIT.…”

Section: Discussionmentioning

confidence: 99%

The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

Gratacap

Martin

Valera

et al. 2009

Blood

111

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Dasatinib is an oral potent adenosine triphosphate (ATP)-competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or Fc␥RIIA cross-linking, which require immunoreceptor tyrosinebased activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by Fc␥RIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology.

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“…For instance, genistein, erbstatin, and tyrphostins inhibit aggregation and secretion induced by ␣-thrombin, collagen, and PAF. [5][6][7][8][9][10] The binding of fibrinogen and the activation-dependent antibody PAC-1 induced by ␣-thrombin and ADP is also abolished. 11 In contrast, other studies could not confirm these observations and emphasized the poor specificity of these inhibitors.…”

mentioning

confidence: 99%

Differential Involvement of Tyrosine and Serine/Threonine Kinases in Platelet Integrin α _IIb β ₃ Exposure

Hers

Donath

Willigen

et al. 1998

ATVB

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Abstract-The relative contributions of protein tyrosine kinases (PTKs) and protein kinase C isoenzymes (PKCs), a family of serine/threonine kinases, in integrin ␣ IIb ␤ 3 (glycoprotein IIb/IIIa) exposure are the subject of much controversy. In the present study we measured the effect of the PTK inhibitor herbimycin A and the PKC inhibitor bisindolylmaleimide I on 125 I-fibrinogen binding to ␣ IIb ␤ 3 and on aggregation/secretion induced by different agonists. Dose-response studies showed complete inhibition of ␣ IIb ␤ 3 exposure by 30 mol/L (ADP stimulation) and 35 to 40 mol/L (␣-thrombin stimulation) herbimycin A. In contrast, inhibition of exposure by bisindolylmaleimide I varied from none (for ADP and epinephrine), to 30% (for platelet-activating factor), and to Ϸ80% (for ␣-thrombin). Studies with a submaximal dose of herbimycin A (Ϸ50% inhibition of the ADP-response) and a maximal dose of bisindolylmaleimide I showed that optical aggregation had a similar sensitivity to the inhibitors as ␣ IIb ␤ 3 exposure with minimal interference by secreted ADP. Thus, the relative contributions of tyrosine and serine/threonine kinases in ␣ IIb ␤ 3 exposure and aggregation differ among the different agonists, with an exclusive role for PTKs in ADP-and epinephrine-induced responses and a role for both PTKs and PKCs in responses induced by platelet-activating factor and ␣-thrombin. (Arterioscler Thromb Vasc Biol. 1998;18:404-414.)Key Words: integrin ␣ IIb ␤ 3 Ⅲ fibrinogen binding Ⅲ aggregation Ⅲ human platelets Ⅲ protein phosphorylation P latelet aggregation is mediated by the coupling of fibrinogen to integrin ␣ IIb ␤ 3 (ie, glycoprotein IIb/IIIa) via binding sites that are exposed when these cells are activated. Our understanding of the intracellular mechanisms that control the exposure of ligand-binding sites on platelet integrin ␣ IIb ␤ 3 is far from complete. A major stimulating pathway in platelets involves tyrosine kinases, which may signal to the processes mediating platelet-platelet contact and formation of focal adhesions.1 A second stimulating route involves hydrolysis of polyphosphoinositides and formation of diacylglycerol, inositol 1,4,5-tris-phosphate, and phosphatidic acid. Diacylglycerol activates PKC, whereas inositol 1,4,5-tris-phosphate mobilizes Ca 2ϩ , thereby inducing rearrangements of the plasma membrane and cytoskeleton that facilitate anchorage of ␣ IIb ␤ 3 and possibly exposure of the binding sites. 1,2There is uncertainty regarding the role of protein kinases in inside-out signaling to ␣ IIb ␤ 3 . Platelet activation is accompanied by tyrosine phosphorylation of 60-, 64-, 75-, and 130-kDa proteins, a step that precedes ligand binding to ␣ IIb ␤ 3 and subsequent outside-in signaling through this integrin. 3,4 One or more of these tyrosine phosphorylations may therefore function in the intracellular control of ␣ IIb ␤ 3 , which accords with the effect of certain PTK inhibitors. For instance, genistein, erbstatin, and tyrphostins inhibit aggregation and secretion induced by ␣-thrombin, collagen, and ...

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Inhibition of platelet activation by tyrosine kinase inhibitors

Cited by 56 publications

References 27 publications

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

Differential Involvement of Tyrosine and Serine/Threonine Kinases in Platelet Integrin α _IIb β ₃ Exposure

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Inhibition of platelet activation by tyrosine kinase inhibitors

Cited by 56 publications

References 27 publications

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-β-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor

The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo

Differential Involvement of Tyrosine and Serine/Threonine Kinases in Platelet Integrin α IIb β 3 Exposure

Contact Info

Product

Resources

About

Differential Involvement of Tyrosine and Serine/Threonine Kinases in Platelet Integrin α _IIb β ₃ Exposure