Histone Deacetylase Inhibitors Trichostatin A and Vorinostat Inhibit TGFβ2-Induced Lens Epithelial-to-Mesenchymal Cell Transition

Xie, Leike; Santhoshkumar, Puttur; Reneker, Lixing W.; Sharma, K. Krishna

doi:10.1167/iovs.14-14109

Cited by 36 publications

(30 citation statements)

References 51 publications

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“…The use of explant cultures has also been applied to the porcine and human lens Xie et al, 2014). These systems have recently been used to demonstrate that histone deacetylase inhibitors can suppress TGFb induced aSMA expression, thus suggesting that epigenetic modifiers could play a role in treating PCO (Xie et al, 2014).…”

Section: Explant Culturesmentioning

confidence: 99%

“…These systems have recently been used to demonstrate that histone deacetylase inhibitors can suppress TGFb induced aSMA expression, thus suggesting that epigenetic modifiers could play a role in treating PCO (Xie et al, 2014). In addition, human lens explants have been employed to understand the possible roles of growth factors, such as HGF and EGF in PCO, through detection of receptors and investigation of signalling pathways (Maidment et al, 2004;Wormstone et al, 2000).…”

Section: Explant Culturesmentioning

confidence: 99%

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Experimental models for posterior capsule opacification research

Wormstone

Eldred

2016

Experimental Eye Research

103

102

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Millions of people worldwide are blinded due to cataract formation. At present the only means of treating a cataract is through surgical intervention. A modern cataract operation involves the creation of an opening in the anterior lens capsule to allow access to the fibre cells, which are then removed. This leaves in place a capsular bag that comprises the remaining anterior capsule and the entire posterior capsule. In most cases, an intraocular lens is implanted into the capsular bag during surgery. This procedure initially generates good visual restoration, but unfortunately, residual lens epithelial cells undergo a wound-healing response invoked by surgery, which in time commonly results in a secondary loss of vision. This condition is known as posterior capsule opacification (PCO) and exhibits classical features of fibrosis, including hyperproliferation, migration, matrix deposition, matrix contraction and transdifferentiation into myofibroblasts. These changes alone can cause visual deterioration, but in a significant number of cases, fibre differentiation is also observed, which gives rise to Soemmering's ring and Elschnig's pearl formation. Elucidating the regulatory factors that govern these events is fundamental in the drive to develop future strategies to prevent or delay visual deterioration resulting from PCO. A range of experimental platforms are available for the study of PCO that range from in vivo animal models to in vitro human cell and tissue culture models. In the current review, we will highlight some of the experimental models used in PCO research and provide examples of key findings that have resulted from these approaches.

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Section: Explant Culturesmentioning

confidence: 99%

Section: Explant Culturesmentioning

confidence: 99%

Experimental models for posterior capsule opacification research

Wormstone

Eldred

2016

Experimental Eye Research

103

102

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“…In addition, aberration in integrin‐mediated cell anchoring has also been implicated in lens epithelial cell EMT (Mamuya et al ., 2014). Recent studies have also shown a role for aldose reductase, MMP, microRNA, and histone deacetylases in lens epithelial cell EMT (Yadav et al ., 2009; Wang et al ., 2013; Korol et al ., 2014; Xie et al ., 2014). …”

Section: Introductionmentioning

confidence: 99%

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

et al. 2016

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SummaryProteins in basement membrane (BM) are long‐lived and accumulate chemical modifications during aging; advanced glycation endproduct (AGE) formation is one such modification. The human lens capsule is a BM secreted by lens epithelial cells. In this study, we have investigated the effect of aging and cataracts on the AGE levels in the human lens capsule and determined their role in the epithelial‐to‐mesenchymal transition (EMT) of lens epithelial cells. EMT occurs during posterior capsule opacification (PCO), also known as secondary cataract formation. We found age‐dependent increases in several AGEs and significantly higher levels in cataractous lens capsules than in normal lens capsules measured by LC‐MS/MS. The TGFβ2‐mediated upregulation of the mRNA levels (by qPCR) of EMT‐associated proteins was significantly enhanced in cells cultured on AGE‐modified BM and human lens capsule compared with those on unmodified proteins. Such responses were also observed for TGFβ1. In the human capsular bag model of PCO, the AGE content of the capsule proteins was correlated with the synthesis of TGFβ2‐mediated α‐smooth muscle actin (αSMA). Taken together, our data imply that AGEs in the lens capsule promote the TGFβ2‐mediated fibrosis of lens epithelial cells during PCO and suggest that AGEs in BMs could have a broader role in aging and diabetes‐associated fibrosis.

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“…TSA is another pan-HDACI similar to SAHA that inhibits HDACs 1, 2, 3, 4, 6, 7, and 10 and showed potent anti-cancer effects in pre-clinical experiments [8, 25–27]. There are pre-clinical studies reporting encouraging results for both SAHA and TSA in the treatment of glioblastomas [18, 19, 28–31]. However, clinical trials showed that the effect was modest, and it is recommended to use HDACIs with other cytotoxic drugs for treating glioblastomas [32, 33].…”

Section: Discussionmentioning

confidence: 99%

A novel histone deacetylase inhibitor, CKD5, has potent anti-cancer effects in glioblastoma

et al. 2016

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There have been extensive efforts to improve the outcome of glioblastoma, but the prognosis of this disease has not been significantly altered to date. Histone deacetylase inhibitors (HDACIs) have been evaluated as promising anti-cancer drugs and regulate cell growth, cell cycle arrest and apoptosis in glioblastoma. Here, we demonstrated the therapeutic efficacy of a novel pan-HDACI, 7-ureido-N-hydroxyheptanamide derivative (CKD5), compared with traditional pan-HDACIs, such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), in vitro and in vivo. Compared with SAHA and TSA, CKD5 had improved cytotoxic effects and induced apoptosis, anti-proliferative activity and cell cycle arrest at G2/M phase. Furthermore, CKD5 significantly reduced tumor volume and prolonged the survival in vivo compared with TSA, suggesting improved anti-cancer efficacy among HDACIs. Our results demonstrate that the novel HDACI CKD5 is a promising therapeutic candidate for glioblastoma.

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Histone Deacetylase Inhibitors Trichostatin A and Vorinostat Inhibit TGFβ2-Induced Lens Epithelial-to-Mesenchymal Cell Transition

Abstract: Histone deacetylase inhibitors, TSA, and SAHA prevent EMT in lens epithelial explants. The results also suggest that the epigenetic modifiers are the potential targets to control PCO after cataract surgery.

Cited by 36 publications

References 51 publications

Experimental models for posterior capsule opacification research

Experimental models for posterior capsule opacification research

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

A novel histone deacetylase inhibitor, CKD5, has potent anti-cancer effects in glioblastoma

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