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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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MC1568 is a selective HDAC inhibitor with IC50 of 220 nM. |
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Targets
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HDAC |
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IC50 |
220 nM [1] |
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In Vitro
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MC1568 is a selective class II (IIa) histone deacetylas (HDAC II) inhibitor with IC50 of 220 nM and 176-fold class II selectivity (against class I). In human breast cancer ZR-75.1 cell lysates, MC1568 (5 μM) shows no inhibitory activity against HDAC1 but is able to inhibit HDAC4. [1]In MCF-7 cells, MC1568 (20 μM) increases the accumulation of acetylated H3 and H4 histones, as well as the levels of acetyl-tubulin, which indicates a inhibitory effect of MC1568 on HDAC6. [2]In C2C12 cells, MC1568 (5 μM) arrests myogenesis by decreasing myocyte enhancer factor 2D (MEF2D) expression, stabilizing the HDAC4-HDAC3-MEF2D complex, and by inhibiting differentiation-induced MEF2D acetylation. [3]MC1568 (5 or 10 μM) interferes with the RAR- and PPARγ-mediated differentiation-inducing signaling pathways. In F9 cells, MC1568 specifically blocks endodermal differentiation despite not affecting retinoic acid-induced maturation of promyelocytic NB4 cells. In 3T3-L1 cells, MC1568 attenuates PPARγ-induced adipogenesis. [4] |
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In Vivo
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In mice, MC1568 (50 mg/kg) shows an apparent tissue-selective HDAC inhibition. In skeletal muscle and heart, MC1568 inhibits the activity of HDAC4 and HDAC5 without affecting HDAC3 activity, thereby leaving MEF2-HDAC complexes in a repressed state. [3]In reporting PPRE-Luc mice, MC1568 (50 mg/kg) impairs PPARγ signaling mostly in the heart and adipose tissues. [4]In a recent study of pancreatic explants, MC1568 enhances expression of Pax4, a key factor required for proper β-and δ-cell differentiation and amplifies endocrine β- and δ-cells. [5] |
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Clinical Trials
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Features
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Protocol
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Kinase Assay
[1]
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| Maize HD2, HD1-B, and HD1-A Enzyme Inhibition. |
The enzyme liberats tritiated acetic acid from the substrate, which is quantified by scintillation counting. IC50 values are results of triple determinations. A 50 μL sample of maize enzyme (at 30 °C) is incubated (30 min) with 10 μL of total [3H]acetate-prelabeled chicken reticulocyte histones (2 mg/mL). Reaction is stopped by addition of 50 μL of 1 M HCl/0.4 M acetate and 800 μL of ethyl acetate. After centrifugation (1×104 g, 5 min), an aliquot of 600 μL of the upper phase is counted for radioactivity in 3 mL of liquid scintillation cocktail. MC1568 is tested at a starting concentration of 40 μM, and active substances are diluted further. NaB, VPA, TSA, SAHA, 85 TPX, HC-toxin, and tubacin are used as the reference compounds, and blank solvents are used as negative controls. |
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Cell Assay
[4]
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| Cell Lines |
3T3-L1 cells |
| Concentrations |
~10 μM, dissolved in DMSO |
| Incubation Time |
8 days |
| Methods |
The 3T3-L1 cells are propagated and differentiated using a cocktail of isobutylmethylxanthine, dexamethasone, and insulin. From the second day post-confluence and throughout the differentiation period of 8 days, the 3T3-L1 cells are induced by: (1) no induction: at post-confluence and throughout the differentiation period of 8 days, the cells are incubated with DMSO or MC1568. (2) troglitazone: at post-confluence and throughout the differentiation period of 8 days, the cells are induced with 5 μM troglitazone, MC1568, or both. (3) rosiglitazone: at post-confluence and throughout the differentiation period of 8 days, the cells are incubated with 1?μM rosiglitazone and either DMSO or MC1568. (4) rosiglitazone and dexamethasone: at post-confluence, the cells received 1?μM of rosiglitazone and 390?ng/mL dexamethasone. Throughout the differentiation period of 8 days, the cells are induced with 1?μM of rosiglitazone and either DMSO or MC1568. All medium is renewed every second day. |
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Animal Study
[4]
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| Animal Models |
PPRE-Luc transgenic mouse (C57BL/6) |
| Formulation |
Dissolved in water solution of 0.5% carbossimetilcellulose |
| Doses |
50 mg/kg |
| Administration |
By gavage once a day |
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References |
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[1] Mai A, et al. J Med Chem, 2005, 48(9), 3344-3353.
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[2] Duong V, et al. Mol Cancer Res, 2008, 6(12), 1908-1919.
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[3] Nebbioso A, et al. EMBO Rep, 2009, 10(7), 776-782.
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[4] Nebbioso A, et al. J Mol Endocrinol, 2010, 45(4), 219-228.
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[5] Lenoir O, et al. Diabetes, 2011, 60(11), 2861-2871.
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