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      Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib

      1 , 2 , 1 , 2

      Drug Design, Development and Therapy

      Dove Medical Press

      kinase inhibitor, lymphangiogenesis, in vitro, in vivo

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          Abstract

          Purpose

          To investigate the feasibility of nintedanib, a novel triple angiokinase inhibitor, for inhibiting lymphatic endothelial cell (LEC)-induced lymphangiogenesis in vitro and inflammatory corneal lymphangiogenesis in vivo.

          Materials and methods

          Methylthiazolyldiphenyl-tetrazolium bromide (MTT) test, transwell system, and tube-formation assay were used to evaluate the effects of nintedanib on the proliferation, migration, and tube formation of LECs stimulated by vascular endothelial growth factor-C (VEGF-C), basic fibroblast growth factor (bFGF), or platelet-derived growth factor-BB (PDGF-BB). The murine model of suture-induced corneal neovascularization was used to assess the anti-hemangiogenic and anti-lymphangiogenic effects of nintedanib via systemic and topical applications. Corneal flatmounts were stained with lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and CD31, and the areas of involved blood and lymph vessels were analyzed morphometrically. Corneal cryosections were stained with F4/80 to evaluate inflammatory cell recruitment.

          Results

          We observed a significant enhanced effect of LEC proliferation, migration, and tube formation with the administration of VEGF-C, PDGF-BB, and bFGF, respectively, which was diminished by nintedanib. Both topical and systemic applications of nintedanib inhibited suture-induced hemangiogenesis and lymphangiogenesis in the murine cornea. A reduction in F4/80 + cell infiltration was observed at day 14 after corneal suture for both systemic and topical applications of nintedanib. In comparison with controls, 61% of F4/80 + cell recruitment was inhibited via the systemic application of nintedanib, while 49% of F4/80 + cell recruitment was inhibited with the topical application of nintedanib.

          Conclusion

          Nintedanib was shown to inhibit in vitro lymphangiogenesis stimulated by VEGF-C, bFGF, and PDGF-BB. Applied topically or systemically, it effectively inhibited corneal hemangiogenesis and lymphangiogenesis, accompanied by reduced inflammatory cell recruitment, which represents a new promising treatment for graft rejection after penetrating keratoplasty.

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          Most cited references 50

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          BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.

          Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.
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            Integrins in angiogenesis and lymphangiogenesis.

            Blood vessels promote tumour growth, and both blood and lymphatic vessels facilitate tumour metastasis by serving as conduits for the transport of tumour cells to new sites. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface receptors whose ligands are extracellular matrix proteins and immunoglobulin superfamily molecules. Select integrins promote endothelial cell migration and survival during angiogenesis and lymphangiogenesis, whereas other integrins promote pro-angiogenic macrophage trafficking to tumours. Several integrin-targeted therapeutic agents are currently in clinical trials for cancer therapy. Here, we review the evidence implicating integrins as a family of fundamental regulators of angiogenesis and lymphangiogenesis.
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              Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.

              Functions of receptor tyrosine kinases implicated in angiogenesis were pharmacologically impaired in a mouse model of pancreatic islet cancer. An inhibitor targeting VEGFRs in endothelial cells (SU5416) is effective against early-stage angiogenic lesions, but not large, well-vascularized tumors. In contrast, a kinase inhibitor incorporating selectivity for PDGFRs (SU6668) is shown to block further growth of end-stage tumors, eliciting detachment of pericytes and disruption of tumor vascularity. Importantly, PDGFRs were expressed only in perivascular cells of this tumor type, suggesting that PDGFR(+) pericytes in tumors present a complimentary target to endothelial cells for efficacious antiangiogenic therapy. Therapeutic regimes combining the two kinase inhibitors (SU5416 and SU6668) were more efficacious against all stages of islet carcinogenesis than either single agent. Combination of the VEGFR inhibitor with another distinctive kinase inhibitor targeting PDGFR activity (Gleevec) was also able to regress late-stage tumors. Thus, combinatorial targeting of receptor tyrosine kinases shows promise for treating multiple stages in tumorigenesis, most notably the often-intractable late-stage solid tumor.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                05 April 2017
                : 11
                : 1147-1158
                Affiliations
                [1 ]Department of Ophthalmology, Eye and ENT Hospital, Fudan University
                [2 ]Key Laboratory of Myopia, Ministry of Health, Shanghai, People’s Republic of China
                Author notes
                Correspondence: Lan Gong, Department of Ophthalmology, Eye and ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, People’s Republic of China, Tel/fax +86 21 6431 0068, Email 13501798683@ 123456139.com
                Article
                dddt-11-1147
                10.2147/DDDT.S130297
                5391212
                © 2017 Lin and Gong. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                in vivo, in vitro, lymphangiogenesis, kinase inhibitor

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