Role of phosphoinositide 3-kinase β in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways

Garcia, Analia; Kim, Soochong; Bhavaraju, Kamala; Schoenwaelder, Simone M.; Kunapuli, Satya P.

doi:10.1042/bj20100166

Cited by 85 publications

(58 citation statements)

References 42 publications

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“…PI3Kb mediates GPCR receptor signaling, regulating thrombinand ADP-mediated platelet aggregation (13,14), as well as LPA receptor-mediated signals via the small GTPase rac (15). Consistent with this, AZD8186 inhibits ADP-induced human platelet aggregation with a mean IC 50 value of 186 nmol/L (Fig.…”

Section: Resultssupporting

confidence: 56%

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Hancox

Cosulich

Hanson

et al. 2015

Molecular Cancer Therapeutics

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Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kb isoform. Inhibitors of PI3Kb have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kb and PI3Kd (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI 50 < 1 mmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kb with activity against PI3Kd signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.

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Section: Resultssupporting

confidence: 56%

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Hancox

Cosulich

Hanson

et al. 2015

Molecular Cancer Therapeutics

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“…PI 3-kinase ␤ has been shown to play an important role in signaling downstream of ␣IIb␤3 (44), and our work has shown that PI 3-kinase ␤ plays an important role in ADP-induced TxA 2 generation (45). Thus, it is possible that Pyk2 mediates ADP-induced TxA 2 generation by regulating PI 3-kinase ␤ activity in platelets.…”

Section: Discussionmentioning

confidence: 74%

Distinct Role of Pyk2 in Mediating Thromboxane Generation Downstream of Both G12/13 and Integrin αIIbβ3 in Platelets

Kim¹,

Cipolla²,

Guidetti³

et al. 2013

Journal of Biological Chemistry

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Background: Pyk2 is abundantly expressed in platelets. Results: Pyk2 regulates thromboxane A 2 generation induced by both 2-methylthio-ADP and AYPGKF. Conclusion: Pyk2 is an important functional tyrosine kinase that is activated by both G 12/13 and integrin ␣IIb␤3 in platelets. Significance: Understanding the mechanism of activation of Pyk2 enhances our understanding of the platelet inside-out and outside-in signaling events.

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“…Platelet granule release is potentiated by P2Y 12 receptor stimulation (Dangelmaier et al, 2001;Garcia et al, 2010). The P2Y 12 receptor gene variants correlate with pulmonary inflammation and asthma (Bunyavanich et al, 2012), and receptor deficiency abrogated dust mite-induced airway inflammation (Paruchuri et al, 2009), suggesting an important role for the P2Y 12 receptor in pulmonary inflammation.…”

Section: Introductionmentioning

confidence: 99%

Prasugrel Metabolites Inhibit Neutrophil Functions

Liverani

Rico

Garcia

et al. 2012

J Pharmacol Exp Ther

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Clopidogrel and prasugrel belong to a thienopyridine class of oral antiplatelet drugs that, after having been metabolized in the liver, can inhibit platelet function by irreversibly antagonizing the P2Y 12 receptor. Furthermore, thienopyridines influence numerous inflammatory conditions, but their effects on neutrophils have not been evaluated, despite the important role of these cells in inflammation. Therefore, we investigated the effect of prasugrel metabolites on neutrophils to further clarify the role of thienopyridines in inflammation. Interestingly, a prasugrel metabolite mixture, produced in vitro using rat liver microsomes, significantly inhibited N-formyl-methionyl-leucylphenylalanine (fMLP)-and platelet-activating factor (PAF)-induced neutrophil activation. More specifically, prasugrel metabolites inhibited neutrophil transmigration, CD16 surface expression, and neutrophil-platelet aggregation. Moreover, prasugrel metabolite pretreatment also significantly decreased fMLP-or PAF-induced extracellular-signal-regulated kinase phosphorylation as well as calcium mobilization. To determine the target of prasugrel in neutrophils, the role of both P2Y 12 and P2Y 13 receptors was studied using specific reversible antagonists, AR-C69931MX and MRS2211, respectively. Neither antagonist had any direct effect on the agonist-induced neutrophil functional responses. Our findings indicate that prasugrel metabolites may directly target neutrophils and inhibit their activation, suggesting a possible explanation for their antiinflammatory effects previously observed. However, these metabolites do not act through either the P2Y 12 or P2Y 13 receptor in neutrophils.

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Role of phosphoinositide 3-kinase β in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways

Cited by 85 publications

References 42 publications

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Distinct Role of Pyk2 in Mediating Thromboxane Generation Downstream of Both G12/13 and Integrin αIIbβ3 in Platelets

Prasugrel Metabolites Inhibit Neutrophil Functions

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