PI3K inhibitors in thrombosis and cardiovascular disease

Durrant, Tom N.; Hers, Ingeborg

doi:10.1186/s40169-020-0261-6

Cited by 61 publications

(48 citation statements)

References 225 publications

(365 reference statements)

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“…Platelets express various PI3K isoforms. The class I PI3Ks, especially PI3Kβ and PI3Kγ, have been widely investigated in arterial thrombosis and cardiovascular disorders, and they are involved in platelet signal transduction during activation [ 67 ]. Recently, class III PI3K α (PI3KC2α) has also been identified in this process, playing a critical role in NOX complex assembly and O•2- production, with PI3KC2α −/− mice showing decreased levels of ROS, reduced shear-dependent platelet adhesion and thrombus stability [ 68 ].…”

Section: Platelet Activation Triggers Ros/ Productionmentioning

confidence: 99%

ROS in Platelet Biology: Functional Aspects and Methodological Insights

Masselli

Pozzi

Vaccarezza

et al. 2020

IJMS

114

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Reactive oxygen species (ROS) and mitochondria play a pivotal role in regulating platelet functions. Platelet activation determines a drastic change in redox balance and in platelet metabolism. Indeed, several signaling pathways have been demonstrated to induce ROS production by NAPDH oxidase (NOX) and mitochondria, upon platelet activation. Platelet-derived ROS, in turn, boost further ROS production and consequent platelet activation, adhesion and recruitment in an auto-amplifying loop. This vicious circle results in a platelet procoagulant phenotype and apoptosis, both accounting for the high thrombotic risk in oxidative stress-related diseases. This review sought to elucidate molecular mechanisms underlying ROS production upon platelet activation and the effects of an altered redox balance on platelet function, focusing on the main advances that have been made in platelet redox biology. Furthermore, given the increasing interest in this field, we also describe the up-to-date methods for detecting platelets, ROS and the platelet bioenergetic profile, which have been proposed as potential disease biomarkers.

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Section: Platelet Activation Triggers Ros/ Productionmentioning

confidence: 99%

ROS in Platelet Biology: Functional Aspects and Methodological Insights

Masselli

Pozzi

Vaccarezza

et al. 2020

IJMS

114

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show abstract

“…11 A second application of this test system might be in patients taking antiplatelet drugs or for risk assessment in cardiovascular diseases. As PI3K inhibitors became more and more important as a therapeutic option in thrombosis and cardiovascular disease, 12 this method might be a diagnostic option for drug monitoring or risk stratification in cardiovascular diseases. 13 Detection of these slight defects in signaling might be helpful in the prediction of bleeding under antiplatelet therapy.…”

Section: Discussionmentioning

confidence: 99%

Flow Cytometric Assessment of AKT Signaling in Platelet Activation: An Alternative Diagnostic Tool for Small Volumes of Blood

et al. 2020

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Introduction The diagnosis of platelet function disorder in children is challenging. Light transmission aggregometry is the gold standard for platelet function disorders. However, large blood volumes are required. Currently, there are no existing tools for the diagnosis of platelet function disorders that use small blood volumes. AKT signaling plays a central role in platelet activation during hemostasis and might be visualized by flow cytometry. Methods Platelet-rich plasma obtained by centrifugation of citrated blood from healthy volunteers was activated with arachidonic acid, thrombin receptor activating peptide-6 (TRAP-6), collagen, adenosine diphosphate ADP, collagen-related peptide (CRP), and epinephrine. After platelet activation, the phosphorylation of AKT was assessed by flow cytometer using a Navios cytometer. Results Healthy volunteers showed a reproducible phosphorylation of AKT upon activation. In comparison to nonactivated platelets, we documented an increase in pAKT expression with all agonists. Especially TRAP-6 and CRP caused considerable increase in percentage of pAKT expression throughout all the tested healthy volunteers. Conclusion An activation of the AKT-signal pathway by different agonists can clearly be detected on the flow cytometer, indicating that the visualization of signaling in platelets by flow cytometry might be an efficient alternative for light transmission aggregometry to test platelet function in children.

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“…Overwhelming information indicates aberrant activation of the PI3K signaling is strongly linked to human cancers [4][5][6][7]. Non-cancerous neurological disorders [19,20], cardiovascular diseases [21][22][23], diabetes [24], immune disorders [17], and CLOVES syndrome characterized by localized tissue outgrowths [25] also share a common etiology with oncogenesis.…”

Section: Class I Phospatidylinositol 3-kinasesmentioning

confidence: 99%

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

Ranganna¹,

Selvam²,

Shivachar³

et al. 2020

IJMS

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Genetic mutations and aberrant epigenetic alterations are the triggers for carcinogenesis. The emergence of the drugs targeting epigenetic aberrations has provided a better outlook for cancer treatment. Histone deacetylases (HDACs) are epigenetic modifiers playing critical roles in numerous key biological functions. Inappropriate expression of HDACs and dysregulation of PI3K signaling pathway are common aberrations observed in human diseases, particularly in cancers. Histone deacetylase inhibitors (HDACIs) are a class of epigenetic small-molecular therapeutics exhibiting promising applications in the treatment of hematological and solid malignancies, and in non-neoplastic diseases. Although HDACIs as single agents exhibit synergy by inhibiting HDAC and the PI3K pathway, resistance to HDACIs is frequently encountered due to activation of compensatory survival pathway. Targeted simultaneous inhibition of both HDACs and PI3Ks with their respective inhibitors in combination displayed synergistic therapeutic efficacy and encouraged the development of a single HDAC-PI3K hybrid molecule via polypharmacology strategy. This review provides an overview of HDACs and the evolution of HDACs-based epigenetic therapeutic approaches targeting the PI3K pathway.

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PI3K inhibitors in thrombosis and cardiovascular disease

Cited by 61 publications

References 225 publications

ROS in Platelet Biology: Functional Aspects and Methodological Insights

ROS in Platelet Biology: Functional Aspects and Methodological Insights

Flow Cytometric Assessment of AKT Signaling in Platelet Activation: An Alternative Diagnostic Tool for Small Volumes of Blood

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

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