Repurposing Ingenol Mebutate as a novel pharmaceutical therapy for normal and pathological dermal fibrosis

Introduction: Excessive dermal scarring/fibrosis poses major challenges to Healthcare Services worldwide.  This is confounded by existing therapies being unsatisfactory at preventing or arresting fibrosis.  Therefore, there is the significant need for novel anti-fibrotic therapies with improved efficacy.  The anti-cancer drug, ingenol mebutate (IngM), is licensed for actinic keratosis and non-melanoma skin cancers.  IngM also stimulates exceptional healing and reduced scarring in treated skin, implying IngM possesses potent anti-fibrotic properties.  As transforming growth factor-β1 (TGF-β1)-driven, dermal fibroblast-myofibroblast differentiation is pivotal to scarring outcomes, fibroblasts and myofibroblasts represent viable IngM targets.  This work evaluated IngM efficacy against normal (dermal) and pathological (keloid) fibroblasts/myofibroblasts; and its mechanisms of action.


Materials and Methods: Human dermal and keloid fibroblasts were treated with IngM (0-10µg/mL) and rhTGF-β1 (10ng/mL); and assessed for myofibroblast differentiation by immunocytochemistry/QRT-PCR for a-smooth muscle actin (α-SMA) expression/stress fibre formation; QRT-PCR/Western blotting of other myofibroblast-/extracellular matrix (ECM)-related genes/proteins; hyaluronan synthesis/assembly (ELISA, hyaluronan synthase QRT-PCR, pericellular localization); and Microarrays/protein validation analysis.


Findings: Although IngM does not inhibit dermal fibroblast-myofibroblast differentiation, IngM alters myofibroblast pro-fibrotic ECM deposition due to enhanced degradation of type I collagen by up-regulated matrix metalloproteinases (MMP-1, MMP-9).  IngM also increases myofibroblast hyaluronan synthesis by hyaluronan synthase-2.  Although reduced MMPs and hyaluronan are hallmarks of keloid scars, increased MMP/hyaluronan levels were also identified in IngM-treated keloid fibroblasts; in addition to reversed keloid fibroblast-myofibroblast formation and reduced type I collagen expression.

Conclusion: Therefore, IngM modulates dermal/keloid fibroblast differentiation and behavior, inducing scar tissue resolution.  Such findings support IngM development/repurposing as a novel anti-fibrotic therapeutic against normal and pathological dermal scarring.

Author: Ryan Moseley, Cardiff University, 

Conference: International Conference on Wound Care, Tissue Repair and Regenerative Medicine
Date & venue: June 14-15, 2018 | London, UK
Website: https://goo.gl/eLcFyZ


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