AR42 (OSU-HDAC42) is an HDAC inhibitor (IC50: 30 nM).

HDAC:30 nM

AR-42通过诱导p21WAF/CIP1表达过量和组蛋白超乙酰化，同时抑制DU-145细胞增长(IC50为0.11 μM)[1]。AR-42能有效抑制PC-3和U87 mg细胞的增殖，部分原因是其下调Akt信号传导的能力[2]。AR-42还能抑制PC-3 (IC50：0.48 μM)和LNCaP (IC50：0.3 μM)细胞的生长。与SAHA相比，AR-42具有明显更高的诱导凋亡能力，并且在PC-3细胞中明显降低Bcl-xL、磷酸化Akt和survivin的水平[3]。在恶性肥大细胞系中，AR-42诱导生长抑制、细胞周期阻滞、凋亡以及caspases-3/7的激活。AR-42下调p-Akt、总Akt、磷酸化STAT3/5 (pSTAT3/5)及总STAT3/5的表达[6]。AR-42有效抑制Raji、JeKo-1和697细胞的增长(IC50<0.61 μM)。AR-42还能通过降低c-FLIP使CLL细胞对TNF-Related Apoptosis-Inducing Ligand (TRAIL)敏感化[7]。AR-42还通过下调Akt/mTOR信号传导和诱导ER应激来诱发自噬。

在PC-3肿瘤异种移植物上，经AR-42（25/50 mg/kg）处理后，肿瘤生长被抑制52%及67%，而SAHA（50 mg/kg）的处理仅能抑制生长31%。与接受SAHA处理的小鼠相比，接受AR-42处理的小鼠的肿瘤内Bcl-xL和pAkt水平显著减少。[3]在转基因小鼠前列腺腺癌（TRAMP）模型中，AR-42不仅降低了前列腺上皮内瘤变（PIN）的严重程度并完全阻止其进展为低分化癌，还促使肿瘤发生向更分化的表型转变，显著抑制了泌尿生殖道绝对（86%）和相对（85%）重量的增加。[5]在三个独立的B细胞恶性疾病小鼠模型中，AR-42显著减少了白细胞计数并延长了生存期，且没有毒性。

In vitro HDAC assay:HDAC activity is analyzed by using an HDAC assay kit. This assay is based on the ability of DU-145 nuclear extract, which is rich in HDAC activity, to mediate the deacetylation of the biotinylated [3H]-acetyl histone H4 peptide that is bound to streptavidin agarose beads. The release of [3H]-acetate into the supernatant is measured to calculate the HDAC activity. Sodium butyrate (0.25-1 mM) is used as a positive control.

Concentrations: Dissolved in DMSO,final concentrations ~2.5 μM. Method: DU-145 Cells are exposed to various concentrations of AR-42 for 96 hours.The medium is removed and replaced by 150 μL of 0.5 mg/mL of MTT in RPMI 1640 medium,and the cells are incubated in the CO2 incubator at 37 °C for 2 hours.Supernatants are removed from the wells,and the reduced MTT dye is solubilized with 200 μL/well of DMSO.Absorbance is determined on a plate reader at 570 nm.

Animal Models: Intact male NCr athymic nude mice inoculated s.c.with PC-3 cells. Formulation: Formulated in methylcellulose/Tween 80. Dosages: ~50 mg/kg/day. Administration: p.o.