Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer.

Autor:	Zwicker JI; Division of Hemostasis and Thrombosis and.; Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Schlechter BL; Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Stopa JD; Division of Hemostasis and Thrombosis and., Liebman HA; Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, California, USA., Aggarwal A; Veterans Affairs Medical Center, Washington, DC, USA., Puligandla M; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Caughey T; Mount Auburn Hospital, Cambridge, Massachusetts, USA., Bauer KA; Division of Hemostasis and Thrombosis and.; Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Kuemmerle N; White River Junction Veterans Affairs Medical Center, White River Junction, Vermont, USA., Wong E; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA., Wun T; Division of Hematology Oncology, University of California Davis School of Medicine, VA Northern California Health Care System, Sacramento, California, USA., McLaughlin M; York Hospital, York, Maine, USA., Hidalgo M; Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Neuberg D; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Furie B; Division of Hemostasis and Thrombosis and., Flaumenhaft R; Division of Hemostasis and Thrombosis and.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2019 Feb 21; Vol. 4 (4). Date of Electronic Publication: 2019 Feb 21 (Print Publication: 2019).
DOI:	10.1172/jci.insight.125851
Abstrakt:	Background: Protein disulfide isomerase (PDI) is a thiol isomerase secreted by vascular cells that is required for thrombus formation. Quercetin flavonoids inhibit PDI activity and block platelet accumulation and fibrin generation at the site of a vascular injury in mouse models, but the clinical effect of targeting extracellular PDI in humans has not been studied. Methods: We conducted a multicenter phase II trial of sequential dosing cohorts to evaluate the efficacy of targeting PDI with isoquercetin to reduce hypercoagulability in cancer patients at high risk for thrombosis. Patients received isoquercetin at 500 mg (cohort A, n = 28) or 1000 mg (cohort B, n = 29) daily for 56 days, with laboratory assays performed at baseline and the end of the study, along with bilateral lower extremity compression ultrasound. The primary efficacy endpoint was a reduction in D-dimer, and the primary clinical endpoint included pulmonary embolism or proximal deep vein thrombosis. Results: The administration of 1000 mg isoquercetin decreased D-dimer plasma concentrations by a median of -21.9% (P = 0.0002). There were no primary VTE events or major hemorrhages observed in either cohort. Isoquercetin increased PDI inhibitory activity in plasma (37.0% in cohort A, n = 25, P < 0.001; 73.3% in cohort B, n = 22, P < 0.001, respectively). Corroborating the antithrombotic efficacy, we also observed a significant decrease in platelet-dependent thrombin generation (cohort A median decrease -31.1%, P = 0.007; cohort B median decrease -57.2%, P = 0.004) and circulating soluble P selectin at the 1000 mg isoquercetin dose (median decrease -57.9%, P < 0.0001). Conclusions: Isoquercetin targets extracellular PDI and improves markers of coagulation in advanced cancer patients. Trial Registration: Clinicaltrials.gov NCT02195232. Funding: Quercegen Pharmaceuticals; National Heart, Lung, and Blood Institute (NHLBI; U54HL112302, R35HL135775, and T32HL007917); and NHLBI Consortium Linking Oncology and Thrombosis (U01HL143365).
Databáze:	MEDLINE
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