Molecule

Description

Multiple myeloma, Lymphoma, Chronic lymphocytic leukaemia

Description

AR-42 (HDAC-42, OSU-HDAC42) is a pan-HDAC inhibitor with IC50 30 nM.

Targets

IC₅₀

In Vitro

AR-42 treatment induces histone hyperacetylation and p21^WAF/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]

In Vivo

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]

Clinical Trials

A Phase I study of AR-42 in treating patients with advanced or relapsed multiple myeloma, chronic lymphocytic leukemia, or lymphoma is currently ongoing.

Features

More potent than SAHA.

Description

Pretreatment of DU-145 cells with 0.25 μM AR-42 augments the effect of bleomycin, doxorubicin, and VP-16, but not 5-FU, on clonogenic inhibition, by targeting Ku70 acetylation. ^[4]

In vitro HDAC assay

HDAC activity is analyzed by using a 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.

Cell Lines

DU-145

Concentrations

Dissolved in DMSO, final concentrations ~2.5 μM

Incubation Time

96 hours

Methods

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 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

Doses

~50 mg/kg/day

Administration

Orally