Low nanomolar concentrations (IC50: 5-20 nM) of Panobinostat (LBH589) induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA damage repair genes including FANCG, FOXO3A, GADD45A, GADD45B, and GADD45G [1]. LBH589 induces acetylation of histone H3 and H4 and of hsp90, increases p21 levels, as well as induces cell-cycle G(1) phase accumulation and apoptosis of the human chronic myeloid leukemia blast crisis (CML-BC) K562 cells and acute leukemia MV4-11 cells with the activating length mutation of FLT-3 [2]. Panobinostat was cytotoxic in almost all 37 cancer cell lines tested. IC50 and LD50 values were in the low nmol/L range (4-470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among the most sensitive lines, with LD(50) values consistently<25 nmol/L [3].

In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy agent etoposide augmented antitumor effects [3]. In all three dosed groups (5, 10 and 20 mg/kg i.p.), panobinostat demonstrated a clear benefit of decreased tumor burden, statistically significant differences were seen for groups treated with 10 and 20 mg/kg doses, as compared with the vehicle control group. Panobinostat treatment also significantly improved TTE, especially at the 20 mg/kg dose [4].

Blasts from peripheral blood of 2 patients and from bone marrow of 4 patients were isolated with Ficoll-Hypaque, put in culture at a density of 500?000 cells/mL with RPMI-1640 medium containing 10% fetal bovine serum and 50 units/mL penicillin and streptomycin, and treated with different doses of LBH589 (0-100 μM) for up to 48 hours [1].

AE17 and TC-1 cancer cells (1 × 10^6 cells) were injected into the flanks of adult female C57Bl/6 mice and severe combined immunodeficiency (SCID) mice. M30 (10 × 10^6 cells), A549 (5 × 10^6 cells), H69 (2.5 × 10^6 cells), BK-T (6.5 × 10^6), H526 (10 × 10^6), and RG1 (10 × 10^6) cells were also injected, but in the presence of matrigel (BD Biosciences), into the flanks of SCID mice. There were 5 to 10 mice in each treatment group. The experiments with the A549 and H69 cell lines were repeated to ensure the statistical consistency of the results. Experiments were terminated when the tumors in the control mice had grown to a size that threatened the quality of life of the mice. When tumors reached 100 to 500 mm3, panobinostat was administered via i.p. injections (10–20 mg/kg) on a daily schedule (5-days-on, 2-days-off regimen) for the entire duration of the experiment. Control mice received i.p. injections with dextrose 5% in water ("vehicle treatment"). Every tumor was measured with a caliper at least twice weekly. For evaluation of the effects of combination therapy on SCLC-derived tumors, SCID mice with H69 tumors were administered panobinostat as described above. Three days after the initiation of panobinostat, and again 1 wk later, etoposide (40 mg/kg) was administered i.p [3].

404950-80-7

C21H23N3O2

349.43

LBH589;NVP-LBH589;帕比司他

H2O:<1 mgml
Ethanol:<1 mgml
DMSO:64 mg/mL (183.2 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years