Evidence map›Paper›PMID 27802516›Full record

ArticleInvestigative ophthalmology & visual science2016

Administration of Menadione, Vitamin K3, Ameliorates Off-Target Effects on Corneal Epithelial Wound Healing Due to Receptor Tyrosine Kinase Inhibition.

Jamie S Rush, David P Bingaman, Paul G Chaney, Martin B Wax, Brian P Ceresa

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Investigative ophthalmology & visual science, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
0.3field-weighted citation impact, top 33% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 16 citations in OpenAlex.

  1. A c-Cbl/Cbl-b antagonist inhibits EGFR ubiquitylation and sustains EGFR phosphorylation to enhance corneal re-epithelialization.Proceedings of the National Academy of Sciences of the United States of America · 2026
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors at 2 institutions in 1 country.

Jamie S RushDepartment of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, United States.
David P BingamanPanOptica, Inc., Bernardsville, New Jersey, United States.
Paul G ChaneyPanOptica, Inc., Bernardsville, New Jersey, United States.
Martin B WaxPanOptica, Inc., Bernardsville, New Jersey, United States 3Department of Ophthalmology and Visual Sciences, Rutgers New Jersey Medical School Newark, New Jersey, United States.
Brian P CeresaDepartment of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, United States 4Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States.
University of Louisville · USRutgers, The State University of New Jersey · US

Funding

Modulation of EGFR Signaling to Promote Corneal Epithelial Wound HealingR01EY021497 · NEI · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · PI CERESA, BRIAN P. · 2012 to 2014
$1.0M
NEI NIH HHS R01 EY021497
6 · The paper itself

Abstract

purposeThe antiangiogenic receptor tyrosine kinase inhibitor (RTKi), 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-[[[[4-(1-pyrrolidinyl) butyl] amino] carbonyl]amino]-4-isothiazolecarboxamide hydrochloride, targets VEGFR2 (half maximal inhibitory concentration [IC50] = 11 nM); however, off-target inhibition of epidermal growth factor receptor (EGFR) occurs at higher concentrations. (IC50 = 5.8 μM). This study was designed to determine the effect of topical RTKi treatment on EGF-mediated corneal epithelial wound healing and to develop new strategies to minimize off-target EGFR inhibition.

methodsIn vitro corneal epithelial wound healing was measured in response to EGF using a transformed human cell line (hTCEpi cells). In vivo corneal wound healing was assessed using a murine model. In these complementary assays, wound healing was measured in the presence of varying RTKi concentrations. Immunoblot analysis was used to examine EGFR and VEGFR2 phosphorylation and the kinetics of EGFR degradation. An Alamar Blue assay measured VEGFR2-mediated cell biology.

resultsReceptor tyrosine kinase inhibitor exposure caused dose-dependent inhibition of EGFR-mediated corneal epithelial wound healing in vitro and in vivo. Nanomolar concentrations of menadione, a vitamin K3 analog, when coadministered with the RTKi, slowed EGFR degradation and ameliorated the inhibitory effects on epithelial wound healing both in vitro and in vivo. Menadione did not alter the RTKi's IC50 against VEGFR2 phosphorylation or its inhibition of VEGF-induced retinal endothelial cell proliferation.

conclusionsAn antiangiogenic RTKi exhibited off-target effects on the corneal epithelium that can be minimized by menadione without deleteriously affecting its on-target VEGFR2 blockade. These data indicate that menadione has potential as a topical supplement for individuals suffering from perturbations in corneal epithelial homeostasis, especially as an untoward side effect of kinase inhibitors.

Indexed as

AnimalsCell LineDisease Models, AnimalEpidermal Growth FactorEpithelium, CornealErbB ReceptorsFemaleHumansMiceMice, Inbred C57BLProtein Kinase InhibitorsProtein-Tyrosine KinasesVascular Endothelial Growth Factor Receptor-2Vitamin K 3Wound HealingEpidermal Growth FactorErbB ReceptorsProtein Kinase InhibitorsProtein-Tyrosine KinasesVascular Endothelial Growth Factor Receptor-2Vitamin K 3

Identifiers

PMID27802516
PMCPMC6733502
OpenAlexW2547954928

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.