The intersection of protein disulfide isomerase and cancer associated thrombosis

Abstract

The mechanisms underlying the hypercoagulability of cancer are complex and include the upregulation coagulation factors or procoagulant proteins, shedding of microparticles, and direct activation of vascular cells. Protein disulfide isomerase (PDI) is a thiol isomerase secreted from activated platelets and endothelial cells and plays a critical role in both platelet aggregation and fibrin generation. A number of potential intravascular targets of PDI have been identified including cell surface receptors (e.g. β-integrins and glycoprotein Ib), receptor ligands (e.g. fibrinogen and von Willebrand factor), serine proteases (e.g. cathepsin G and kallekrein-14), and coagulation factors (e.g. factor XI and factor V). Recent clinical studies demonstrated that a small molecule inhibitor of PDI, isoquercetin, decreases platelet-dependent thrombin generation and PDI activity in plasma following oral administration. This review explores the mechanistic overlap between the molecular drivers of cancer associated thrombosis and the potential roles PDI plays in mediating thrombosis. These molecular insights provide rationale for clinical trials targeting PDI to prevent thrombosis in cancer patients.

PDIA4 Correlates with Poor Prognosis and is a Potential Biomarker in Glioma

“…PDIA4 was originally described to be involved in various biological processes, including coagulation, 33 thrombosis formation 34 , 35 and injury reaction. 36 Recently, there has been a mounting evidence that aberrant expression and the potential mechanisms of PDIA4 participate in the development of multiple types of cancer.…”

Molecular docking‐assisted screening reveals tannic acid as a natural protein disulphide isomerase inhibitor with antiplatelet and antithrombotic activities

“…As PDI mediates the formation of free thiols in key activation receptors on platelet surface and promotes platelet activation, 32 Figure 2F). Therefore, TA, within the tested concentration ranges, does not induce platelet apoptosis.…”

Novel Antiplatelet Therapies for Atherothrombotic Diseases

“…PDI (protein disulfide-isomerase) exist in platelet granules and the platelet surface where they are involved in thrombosis through their action on several intravascular targets. 53,54 PDI inhibitors in preclinical studies have been shown to reduce platelet aggregation and reduce thrombus formation under flow conditions, and have been shown to protect mice from carotid artery occlusion. 54 The PDI inhibitor isoquercetin underwent phase I clinical study and was shown to diminish platelet-dependent thrombin generation by blocking generation of platelet factor Va. 55 Isoquercetin is currently in phase II/III clinical study to evaluate its potential role in preventing venous thrombosis in patients with pancreatic, nonsmall cell lung, or colorectal cancer (http://www.clinicaltrials.gov.…”