PUBLICATION
Inhibition of cell migration and induction of apoptosis by a novel class II histone deacetylase inhibitor, MCC2344
- Authors
- Dawood, M., Fleischer, E., Klinger, A., Bringmann, G., Shan, L., Efferth, T.
- ID
- ZDB-PUB-200715-16
- Date
- 2020
- Source
- Pharmacological research 160: 105076 (Journal)
- Registered Authors
- Keywords
- Drug development, Epigenetics, Leukemia, Microscale thermophoresis, Targeted chemotherapy, Virtual drug screening, Zebrafish
- MeSH Terms
-
- Acetylation
- Animals
- Antineoplastic Agents/pharmacology*
- Apoptosis/drug effects*
- Apoptosis Regulatory Proteins/metabolism
- Cell Movement/drug effects*
- Cyclohexenes/pharmacology*
- Epigenesis, Genetic/drug effects
- HSP90 Heat-Shock Proteins/metabolism
- Histone Deacetylase 6/antagonists & inhibitors*
- Histone Deacetylase 6/metabolism
- Histone Deacetylase Inhibitors/pharmacology*
- Humans
- MCF-7 Cells
- Microtubules/drug effects
- Microtubules/metabolism
- Microtubules/pathology
- Neoplasm Invasiveness
- Neoplasms/drug therapy*
- Neoplasms/enzymology
- Neoplasms/genetics
- Neoplasms/pathology
- Tubulin/metabolism
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 32659428 Full text @ Pharmacol. Res.
Citation
Dawood, M., Fleischer, E., Klinger, A., Bringmann, G., Shan, L., Efferth, T. (2020) Inhibition of cell migration and induction of apoptosis by a novel class II histone deacetylase inhibitor, MCC2344. Pharmacological research. 160:105076.
Abstract
Epigenetic modifiers provide a new target for the development of anti-cancer drugs. The eraser histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase that targets various non-histone proteins such as transcription factors, nuclear receptors, cytoskeletal proteins, DNA repair proteins, and molecular chaperones. Therefore, it became an attractive target for cancer treatment. In this study, virtual screening was applied to the MicroCombiChem database with 1,162 drug-like compounds to identify new HDAC6 inhibitors. Five compounds were tested in silico and in vitro as HDAC6 inhibitors. Both analyses revealed 1-cyclohexene-1-carboxamide, 2-hydroxy-4,4-dimethyl-N-1-naphthalenyl-6-oxo- (MCC2344) as the best HDAC6 inhibitor among the five ligands. The binding affinity of MCC2344 to HDAC6 was further confirmed by microscale thermophoresis. Additionally, the anti-cancer activity of MCC2344 was tested in several tumor cell lines. Leukemia cells were the most sensitive cells towards MCC2344, particularly the P-glycoprotein-overexpressing multidrug-resistant cell line CEM/ADR5000 exhibited remarkable collateral sensitivity towards MCC2344. Transcriptome analysis using microarray hybridization was performed for investigating downstream mechanisms of action of MCC2344 in leukemia cells. MCC2344 affected microtubule dynamics and suppressed cell migration in the wound healing assay as well as in a spheroid model by hyper-acetylation of tubulin and HSP-90. MCC2344 induced cell death in CEM/ADR5000 cells by activation of PARP, caspase-3, and p21 in addition to the downregulation of p62. MCC2344 significantly inhibited tumor growth in vivo in zebrafish larvae without mortality until 20 pM. We propose MCC2344 as a novel HDAC6 inhibitor for cancer treatment.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping