The thrombin inhibitor, argatroban, inhibits breast cancer metastasis to bone

Asanuma, Kunihiro; Wakabayashi, Hiroki; Okamoto, Takayuki; Asanuma, Yumiko; Akita, Nobuyuki; Yoshikawa, Tomoaki; Hayashi, Tatsuya; Matsumine, Akihiko; Uchida, Atsushi; Sudo, Akihiro

doi:10.1007/s12282-012-0334-5

Cited by 25 publications

(24 citation statements)

References 28 publications

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“…Although the mechanisms of intestinal radiation protection by Solulin require further investigation, Solulin's thrombin-inhibiting properties likely play a significant role in this regard, as we have shown previously that the thrombin inhibitor hirudin attenuates structural and molecular aspects of intestinal radiation injury (13). Moreover, thrombin inhibition is also known to suppress cancer cell growth (58); therefore, Solulin would be expected to reduce rather than enhance cancer growth, thereby increasing the therapeutic ratio of radiotherapy. A phase I trial of Solulin showed excellent overall tolerability (in dose ranges of 0.6–30 mg for single or multiple dose; 1–10 mg once daily for five days) with no bleeding risk, linear pharmacokinetics, dose-dependent thrombin inhibition and long plasma half-life (15–30 h) (21).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model

Pathak¹,

Wang²,

Garg³

et al. 2016

Radiation Research

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Intestinal radiation toxicity occurs during and after abdominopelvic radiotherapy. Endothelial cells play a significant role in modulating radiation-induced intestinal damage. We demonstrated that the endothelial cell surface receptor thrombomodulin (TM), a protein with anticoagulant, antiinflammatory and antioxidant properties, mitigates radiation-induced lethality in mice. The goal of this study was to determine whether recombinant TM (Solulin) can protect the intestine from toxicity in a clinically relevant rat model. A 4 cm loop of rat small bowel was exposed to fractionated 5 Gy X radiation for 9 consecutive days. The animals were randomly assigned to receive daily subcutaneous injections of vehicle or Solulin (3 mg/kg/day or 10 mg/kg/day) for 27 days starting 4 days before irradiation. Early intestinal injury was assessed two weeks after irradiation by quantitative histology, morphometry, immunohistochemistry and luminol bioluminescence imaging. Solulin treatment significantly ameliorated intestinal radiation injury, made evident by a decrease in myeloperoxidase (MPO) activity, transforming growth factor beta (TGF-β) immunoreactivity, collagen-I deposition, radiation injury score (RIS) and intestinal serosal thickening. These findings indicate the need for further development of Solulin as a prophylactic and/or therapeutic agent to mitigate radiation-induced intestinal damage.

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Section: Discussionmentioning

confidence: 99%

Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model

Pathak¹,

Wang²,

Garg³

et al. 2016

Radiation Research

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“…Thrombin-mediated PAR activation has been implicated in vascular smooth muscle cell migration and proliferation as causative processes in restenosis after stent placement [44], and in tumor metastasis, where a simultaneous requirement for PARs and fibrinogen was found [45]. Thrombosis and cancer have since long been recognized as interconnected pathologies, and in this light argatroban, the tight-binding competitive inhibitor of active thrombin, has been re-evaluated as a clinically useful antiproliferative and antimetastatic agent [46]. …”

Section: Regulation Of Physiological Processesmentioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

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Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

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“…However, heparin is extremely sensitive to induce thrombocytopenia and thrombosis, so it is necessary to find a new anticoagulant to overcome the shortcomings of heparin. Argatroban (AG), a small‐molecule derivative of arginine, inhibits thrombin activation directly with reliable and predictable anticoagulant actions, which has already been used in the clinical setting as thrombin inhibitor . AG can substitute heparin in patients in whom the use of heparin is contraindicated, because it can treat heparin‐induced thrombocytopenia effectively .…”

Section: Introductionmentioning

confidence: 99%

“…Argatroban (AG), a small-molecule derivative of arginine, inhibits thrombin activation directly with reliable and predictable anticoagulant actions, which has already been used in the clinical setting as thrombin inhibitor. 43 AG can substitute heparin in patients in whom the use of heparin is contraindicated, because it can treat heparin-induced thrombocytopenia effectively. 44 By comparison with traditional anticoagulants such as heparin and warfarin, AG is a more potent inhibitor of bound thrombin than heparin or low molecular weight heparins, and the mechanism action of AG is less complex than that of warfarin.…”

Section: Introductionmentioning

confidence: 99%

Dual functionalized poly(vinylidene fluoride) membrane with acryloylmorpholine and argatroban to improve antifouling and hemocompatibility

Feng

et al. 2016

J Biomedical Materials Res

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The present work aims to improve the antifouling properties and anticoagulation of poly(vinylidene fluoride) (PVDF) membrane by dual modification. An amphiphilic copolymer of PVDF-g-(polyacryloylmorpholine-(polyacrylic acid)) [PVDF-g-(PACMO-PAA)] was first prepared by the free radical copolymerization. Then argatroban, a commonly used anticoagulant, was successfully grafted to PVDF-g-(PACMO-PAA). Finally the obtained copolymer was casted into a flat membrane via immersion phase inversion. The as-prepared copolymer membranes show improved hydrophilicity, higher water flux and lower protein adsorption. Moreover, the hemolysis and coagulation tests for the dual functionalized PVDF membrane exhibit decreased hemolysis ratio, with prolonged plasma recalcification time, activated partial thromboplastin time and thrombin time. PVDF membrane incorporating PACMO and AG reveals an improved hemocompatibility, which has a good potential to be used in blood purification. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 178-188, 2017.

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The thrombin inhibitor, argatroban, inhibits breast cancer metastasis to bone

Cited by 25 publications

References 28 publications

Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model

Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model

Proteases: Pivot Points in Functional Proteomics

Dual functionalized poly(vinylidene fluoride) membrane with acryloylmorpholine and argatroban to improve antifouling and hemocompatibility

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