Abstract
To evaluate the potential utility of histone deacetylase inhibitors (HDACi) for treatment of retinoblastoma (RB). Growth-inhibitory effects of HDACi [trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), or MS-275] were assessed in human and transgenic murine RB cells. Effects of TSA and MS-275 were also assessed in combination with standard therapeutic agents for RB. Proapoptotic effects of MS-275 and TSA were evaluated by caspase-3/7 activity, Annexin V translocation, and/or Bim expression analyses. Effects of MS-275 on cell cycle distribution and reactive oxygen species levels were determined by flow cytometry. Retinal tissue morphology was evaluated in mice after local administration of MS-275. Analysis of retinal acetyl-histone levels was used to assess MS-275 delivery after systemic administration. Therapeutic effects of MS-275 were determined in transgenic mouse and rat ocular xenograft models of RB after i.p. injection of 20 mg/kg every other day for 21 or 13 days, respectively. TSA, SAHA, and MS-275 dose dependently reduced RB cell survival. TSA and MS-275 showed additive growth-inhibitory effects in combination with carboplatin, etoposide, or vincristine. TSA and MS-275 increased caspase-3/7 activity. MS-275 increased Annexin V membrane translocation and induced G1 arrest. Cytotoxicity of MS-275 was dependent on increased reactive oxygen species levels and was reversed by antioxidant pretreatment. Intraocular administration of 1 microL of 10 micromol/L MS-275 did not alter ocular tissue morphology. Increased acetyl-histone levels confirmed MS-275 delivery to retinal tissue after systemic administration. MS-275 significantly reduced tumor burden in both mouse and rat models of RB. HDACi should be considered for clinical trials in children with RB.
Highlights
To evaluate the potential utility of histone deacetylase inhibitors (HDACi) for treatment of retinoblastoma (RB)
We further evaluated the effects of histone deacetylases (HDACs) inhibition in established and primary human RB cell cultures using three HDACi: trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and MS-275
Y79 cells were treated for 8 h with TSA, SAHA, or MS-275, and cell extracts were analyzed for increased acetylation of histone H3 at Lys9 by Western blot analysis
Summary
To evaluate the potential utility of histone deacetylase inhibitors (HDACi) for treatment of retinoblastoma (RB). Experimental Design: Growth-inhibitory effects of HDACi [trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), or MS-275] were assessed in human and transgenic murine RB cells. Proapoptotic effects of MS-275 and TSA were evaluated by caspase-3/7 activity, Annexin V translocation, and/or Bim expression analyses. Effects of MS-275 on cell cycle distribution and reactive oxygen species levels were determined by flow cytometry. Retinal tissue morphology was evaluated in mice after local administration of MS-275. Analysis of retinal acetyl-histone levels was used to assess MS-275 delivery after systemic administration. Therapeutic effects of MS-275 were determined in transgenic mouse and rat ocular xenograft models of RB after i.p. injection of 20 mg/kg every other day for 21or 13 days, respectively. Increased acetyl-histone levels confirmed MS-275 delivery to retinal tissue after systemic administration. Conclusions: HDACi should be considered for clinical trials in children with RB
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