Vorinostat (SAHA)

264, 3

Male BALB/c nude (nu/nu) mice implanted with CWR22 tumor cells

A Phase I/II study of Vorinostat on HIV RNA expression in the resting CD4+ T cells of HIV-infected patients receiving stable antiretroviral therapy is currently ongoing.

ca.100 mg/kg/day

ca.10 nM [1], ca.10 nM [1], ca.10 nM [1], ca.10 nM [1], ca.10 nM [1], ca.10 nM [1]

Administration of Vorinostat (ca.100 mg/kg/day) significantly inhibits the growth of CWR22 human prostate xenografts in nude mice with tumor reductions of 78%, 97% and 97%, at doses of 25 mg/kg/day, 50 mg/kg/day and 100 mg/kg/day, respectively, compared with control. Vorinostat induces the accumulation of acetylated core histones and prostate-specific antigen mRNA expression in CWR22 cells, resulting in higher levels of serum prostate-specific antigen than predicted from tumor volume alone. [2] Oral administration of Vorinostat (0.67g/L) crosses the blood-brain barrier, increases histone acetylation in the brain, and dramatically improves the motor impairment in the R6/2 mice model of Huntington's disease. [5]

Immunoprecipitation-HDAC assays, The lysate of Jurkat cells is incubated for 1 hour on ice and cleared by centrifugation at 12, 000 g for 10 minutes at 4 C. Supernatants are precleared with 30 uL of 50% protein G-Sepharose slurry for 1 hour at 4 C. Beads are pelleted by centrifugation and supernatants are incubated for 1 hour at 4 C with 10 ug of IgG fraction from anti-HDAC1 or HDAC3 polyclonal antisera (preincubated 2 hours at room temperature with either the homologous or heterologous immunizing peptide). Both antisera are raised in rabbits against the carboxylterminal peptide of HDAC1 and HDAC3 by using synthetic peptides coupled to keyhole limpet hemocyanin. 30 uL of 50% protein G-Sepharose slurry is added for 1 hour at 4 C. Immune complexes are pelleted by centrifugation and washed three times with 1 mL of lysis buffer. Beads are resuspended in 200 uL of HDAC buffer (20 mM Tris-HCl, pH 8.0/150 mM NaCl/10% glycerol), and the HDAC assay is performed with an 3H-acetylated peptide corresponding to amino acids 1-24 of histone H4. Released [3H]acetic acid is quantified by scintillation counting. For inhibitions studies, the immunoprecipitated complexes are preincubated with the different concentrations of Vorinostat for 30 minutes at 4 C.

DMSO 53 mg/mL, Water <1 mg/mL, Ethanol 3 mg/mL