Efficacy and safety of suberoylanilide hydroxamic acid (Vorinostat) in the treatment of canine corneal fibrosis

Abstract

Suberoylanilide hydroxamic acid safely and effectively inhibits TGFβ1-induced CCFs transformation to myofibroblast in vitro.

Suberoylanilide hydroxamic acid (vorinostat): its role on equine corneal fibrosis and matrix metalloproteinase activity

“…Similar to the present study, others have also demonstrated that the addition of TGFβ inhibits keratocyte proliferation in vitro . Myofibroblasts are highly contractile cells with decreased intracellular crystalline production resulting in decreased corneal transparency . Silencing of HDAC4 with short interrupting RNA (siRNA) prevents TGFβ‐mediated transdifferentiation of skin fibroblasts into myofibroblasts implicating HDAC in TGFβ‐mediated fibrosis .…”

“…Recently, we have demonstrated the inhibition of corneal haze in rabbits with trichostatin A (TSA) as well as SAHA, both of which are HDAC inhibitors . We have also recently demonstrated effective inhibition of canine corneal fibrosis in vitro using SAHA . TSA is still under clinical trial and is not routinely used in the clinical setting to treat patients.…”

Development of a novel in vivo corneal fibrosis model in the dog

“…al. found that SAHA reduced corneal haze in rabbits in vivo following PRK (Bosiack et al 2012, Tandon et al 2012, Donnelly et al 2014). While the efficacy of SAHA as an anti-fibrotic has been repeatedly demonstrated, the precise molecular mechanisms by which it inhibits fibrosis in the cornea have not been extensively investigated so far.…”

“…H&E sections of the affected corneas revealed that the cellularity of the superficial stroma was markedly increased. Although a minority of these stromal cells stained positively for CD18, suggesting an inflammatory lineage, it appeared that the majority of cells stained positively for α-SMA, a known hallmark of fibrosis (Buss et al 2010, Bosiack, Giuliano et al 2012). This staining for α-SMA was significantly increased in the alkali-burned corneas when compared to control corneas, thereby suggesting that the alkali burn induced the transdifferentiation of corneal fibroblasts to myofibroblasts.…”

“…For instance, trichostatin A, an inhibitor of class I and II HDACs, was shown to effectively decrease corneal fibrosis in rabbits in vivo following photorefractive keratectomy surgery (Sharma et al 2009). Another HDACi, suberanilohydroxamic acid (SAHA) which is FDA approved, tested in our laboratory demonstrated significant inhibition of TGF-β1-mediated fibrosis in canine and equine cornea in vitro and rabbit cornea in vivo (Bosiack et al 2012, Tandon et al 2012, Donnelly et al 2014). A recent study from our laboratory found that anti-fibrotic effects of SAHA are partially mediated by the transcriptional repressors 5′TG3′-interacting factors (TGIF) 1 and TGIF2 in human cornea in vitro (Sharma et al 2015).…”