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生物活性
产品描述
AR-42是一种HDAC抑制剂，IC50为30 nM。
靶点
HDAC
 
 
 
 
 
IC50
30 nM [1]
 
 
 
 
 
体外研究
AR-42 treatment induces histone hyperacetylation and p21WAF/CIP1 overexpression, and inhibits the growth of DU-145 cells with IC50 of 0.11 μM. [1] HDAC42 is potent in suppressing the proliferation of U87MG and PC-3 cells, in part, because of its ability to down-regulate Akt signaling. [2] AR-42 inhibits the growth of PC-3 and LNCaP cells with IC50 of 0.48 μM and 0.3 μM, respectively. Compared to SAHA, AR-42 exhibits distinctly superior apoptogenic potency, and causes markedly greater decreases in phospho-Akt, Bcl-xL, and survivin in PC-3 cells. [3] AR-42 treatment induces growth inhibition, cell- cycle arrest, apoptosis, and activation of caspases-3/7 in malignant mast cell lines. AR-42 treatment induces down-regulation of Kit via inhibition of Kit transcription, disassociation between Kit and heat shock protein 90 (HSP90), and up-regulation of HSP70. AR-42 treatment down-regulates the expression of p-Akt, total Akt, phosphorylated STAT3/5 (pSTAT3/5), and total STAT3/5. [6] AR-42 potently inhibits the growth of JeKo-1, Raji, and 697 cells with IC50 of <0.61 μM. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. [7] AR-42 treatment also induces autophagy through downregulation of Akt/mTOR signaling and inducing ER stress in hepatocellular carcinoma (HCC) cells. [8]
体内研究
The growth of PC-3 tumor xenografts is suppressed by 52% and 67% after treatment with AR-42 at 25 mg/kg and 50 mg/kg, respectively, whereas SAHA at 50 mg/kg suppresses growth by 31%. In contrast to mice treated with SAHA, intratumoral levels of phospho-Akt and Bcl-xL are markedly reduced in AR-42 treated mice. [3] In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, administration of AR-42 not only decreases the severity of prostatic intraepithelial neoplasia (PIN) and completely prevents its progression to poorly differentiated carcinoma, but also shifts tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively. [5] AR-42 significantly reduces leukocyte counts, and prolongs survival in three separate mouse models of B-cell malignancy without evidence of toxicity. [7]
特征
More potent than SAHA.
推荐的实验操作(此推荐来自于公开的文献所以Selleck并不保证其有效性)
激酶实验: 
[1]
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.
细胞试验: 
[1]
细胞系
DU-145
浓度
Dissolved in DMSO, final concentrations ~2.5 μM
处理时间
96 hours
方法
Cells are exposed to varous 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 CO2incubator 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.
动物实验: 
[3]
动物模型
Intact male NCr athymic nude mice inoculated s.c. with PC-3 cells
配制
Formulated in methylcellulose/Tween 80
剂量
~50 mg/kg/day
给药处理
Orally
溶解度
0.5% methylcellulose/0.2% Tween 80, 30 mg/mL
参考文献
[1] Lu Q, et al. J Med Chem, 2005, 48(17), 5530-5535.
[2] Chen CS, et al. J Biol Chem, 2005, 280(46), 38879-38887.
[3] Kulp SK, et al. Clin Cancer Res, 2006, 12(17), 5199-5206.
[4] Chen CS, et al. Cancer Res, 2007, 67(11), 5318-5327.
[5] Sargeant AM, et al. Cancer Res, 2008, 68(10), 3999-4009.
[6] Lin TY, et al. Blood, 2010, 115(21), 4217-4225.
[7] Lucas DM, et al. PLoS One, 2010, 5(6), e10941.
[8] Liu YL, et al. Autophagy, 2010, 6(8), 1057-1065.