AR-42 is a novel HDAC inhibitor with an IC50 of 0.61 μM for acute lymphoblastic leukemia (697) cell lines. In chronic lymphocytic leukemia (CLL) cells, the 48-hr LC50 of AR-42 is 0.76 μM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity. AR-42 has in vitro and in vivo efficacy at tolerable doses. In additon, AR-42 promoted hyperacetylation of H3, H4, and alpha-tubulin, and up-regulation of p21. Down-regulation of Kit occurred after AR-42 爐reatment via inhibition of Kit transcription.
|Preparation method||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.|
|Concentrations||Dissolved in DMSO, final concentrations ~2.5 μM|
|Incubation time||96 hours|
|Animal models||Intact male NCr athymic nude mice inoculated s.c. with PC-3 cells|
|Formulation||Formulated in methylcellulose/Tween 80|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 60 mg/mL|
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