Suppression of insulin-like growth factor signalling pathway and collagen expression in keloid-derived fibroblasts by quercetin: its therapeutic potential use in the treatment and/or prevention of keloids.
BACKGROUND
Keloids are characterized by abnormal proliferation of fibroblasts and overproduction of collagen. Insulin-like growth factor (IGF)-I is mitogenic for fibroblasts and a stimulatory factor for collagen synthesis.


OBJECTIVE
We have assessed the in vitro effects of quercetin on proliferation, collagen synthesis and the expression of the IGF system in keloid-derived fibroblasts.


METHODS
Fibroblasts were isolated from earlobe keloids and exposed to quercetin at different concentrations. The inhibitory effects of quercetin on fibroblast proliferation were assayed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Western and Northern blot analyses.


RESULTS
Quercetin inhibited keloid fibroblast (KF) proliferation in a dose-dependent manner. Significant growth inhibition was observed on day 2 of culture. The dose required for 50% growth inhibition was approximately 25 microg mL-1. Collagen 1 expression was significantly decreased while collagen 3 was almost undetectable following quercetin treatment. Basal levels of IGF-I receptor (IGF-IR) beta subunits, p85 subunit of phosphatidylinositol 3-kinase, c-Raf, phospho-Raf-1, phospho-MEK 1/2, phospho-mitogen-activated protein kinase, phospho-Elk-1 and phospho-Akt-1 were significantly reduced when KF cells were exposed to quercetin for 24 h. Blocking IGF-IR activity with IGF-IR antibody or neutralizing endogenous IGF-I activity with IGF-I antibody led to significant growth inhibition suggesting the role of IGF-I in regulation of KF proliferation.


CONCLUSIONS
Because the IGF system plays an important part in fibroblast cell proliferation and collagen production, the described activities of quercetin on the IGF system and collagen expression may provide a novel approach for the use of quercetin in treatment and/or prevention of hypertrophic scar and keloid.
Phan
T T
TT
Department of Plastic Surgery, Singapore General Hospital, Singapore.
See
P
P
Tran
E
E
Nguyen
T T T
TT
Chan
S Y
SY
Lee
S T
ST
Huynh
H
H
D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000187:drug effects* / Q000378:metabolism; D007627:Keloid / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D010750:Phosphoproteins / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis; D011794:Quercetin / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000187:drug effects* / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D011794:Quercetin; D017526:Receptor, IGF Type 1; D019908:Proto-Oncogene Proteins c-raf