Vorinostat (SAHA) efficiently suppressed MES-SA cell growth at a low dosage (3 μM) already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 μM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours [1]. SAHA inhibits HDAC1 and HDAC3 activity in vitro. Treatment of cells in culture with SAHA results in a marked hyperacetylation of histone H4 [2]. The concentrations of SAHA of ≥2.5 μM caused profound growth arrest. The IC50 of 0.75 μM was calculated as 50% reduction in cell number after 120 h of continuous exposure to SAHA. Cell cycle analysis evaluated after 48 h exposure to SAHA showed an accumulation of cells predominantly in G1 at low concentrations (1.25 and 2.5 μM) [3].

Nude mice injected with 5 x 10^6 MES-SA cells were treated for 21 days with vorinostat (50 mg/kg/day) and, in comparison to placebo group, a tumor growth reduction of more than 50% was observed [1]. For comparison, 100 mg/kg SAHA in either HOP-β-CD or DMSO was administered to WT and R6/2 by single i.p. injection. It had no difference in the degree of histone acetylation between untreated WT and R6/2 mice. Significant increases in histone acetylation could be detected only on s.c. administration of 200 mg/kg [4].

Cells were plated onto 100-mm tissue culture plates at a density of 2 × 10^6 for 48 h and then treated with SAHA or equal concentrations of the vehicle. For longer drug exposure times, medium with drug or vehicle were exchanged every 48 h. For wash-out experiments, cells were treated with SAHA daily for 60–72 h (drug and medium were exchanged at 48 h), then SAHA was washed out and replaced with 10% FCS containing DMEM [3].

Athymic Nude-Foxn1nu/nu mice were used in the present study. They were housed at 22°C at a constant light-dark cycle (12-h light, 12-h dark) and had free access to water and rodent chow (4-5% fat, 21% protein). Twelve weeks old male mice (n = 14) were anesthetized with Isofluran and 5 × 10^6 MES-SA cells were injected subcutaneously into the right flank of the animal. Mice from a control group received placebo containing 300 μl of empty HOP-β-CD (2-hydroxypropyl-β-cyclodextrin) vesicles. Another group of mice received vorinostat dissolved in HOP-β-CD at a concentration of 50 mg/kg/day. Both, empty vesicles and vorinostat were administered intraperitoneally, starting on the day 4 after the injection of MES-SA tumor cells. Mice body weight and tumor size (w2 × l × 0.52; measured by caliper) were estimated twice a week. All mice were treated for 21 days and afterward sacrificed by cervical dislocation. Each tumor was isolated as a whole and different tumor parameters (weight, volume, size, and macroscopic appearance) were determined. Finally, tumor slices were cryopreserved and formalin fixed (4%) for further analyses [1].

149647-78-9

C14H20N2O3

264.325

伏立诺他;suberoylanilide hydroxamic acid;MK0683;SAHA

DMSO:53 mg/mL (200.52 mM)
Ethanol:2 mg/mL(7.6 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years