Inhibition of cell migration and induction of apoptosis by a novel class II histone deacetylase inhibitor, MCC2344
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Mona Dawood
- Edmond Fleischer
- Anette Klinger
- Gerhard Bringmann
- Letian Shan
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000598125100012&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.phrs.2020.105076
- Externe Identifier
- Clarivate Analytics Document Solution ID: PE1IO
- PubMed Identifier: 32659428
- ISSN
- 1043-6618
- Zeitschrift
- PHARMACOLOGICAL RESEARCH
- Schlüsselwörter
- Drug development
- Epigenetics
- Leukemia
- Microscale thermophoresis
- Targeted chemotherapy
- Virtual drug screening
- Zebrafish
- Artikelnummer
- ARTN 105076
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Titel
- Inhibition of cell migration and induction of apoptosis by a novel class II histone deacetylase inhibitor, MCC2344
- Sub types
- Article
- Ausgabe der Zeitschrift
- 160
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Autoren
- Mona Dawood
- Edmond Fleischer
- Anette Klinger
- Gerhard Bringmann
- Letian Shan
- Thomas Efferth
- DOI
- 10.1016/j.phrs.2020.105076
- ISSN
- 1043-6618
- Zeitschrift
- Pharmacological Research
- Sprache
- en
- Artikelnummer
- 105076
- Paginierung
- 105076 - 105076
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.phrs.2020.105076
- Datum der Datenerfassung
- 2020
- Titel
- Inhibition of cell migration and induction of apoptosis by a novel class II histone deacetylase inhibitor, MCC2344
- Ausgabe der Zeitschrift
- 160
Datenquelle: Crossref
- 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 1162 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.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany; Department of Molecular Biology, Faculty of Medical Laboratory Sciences, Al-Neelain University, Khartoum, Sudan.
- Autoren
- Mona Dawood
- Edmond Fleischer
- Anette Klinger
- Gerhard Bringmann
- Letian Shan
- Thomas Efferth
- DOI
- 10.1016/j.phrs.2020.105076
- eISSN
- 1096-1186
- Externe Identifier
- PubMed Identifier: 32659428
- Open access
- false
- ISSN
- 1043-6618
- Zeitschrift
- Pharmacological research
- Schlüsselwörter
- Microtubules
- Animals
- Zebrafish
- Humans
- Neoplasms
- Neoplasm Invasiveness
- Tubulin
- Antineoplastic Agents
- Xenograft Model Antitumor Assays
- Apoptosis
- Cell Movement
- Epigenesis, Genetic
- Acetylation
- HSP90 Heat-Shock Proteins
- Apoptosis Regulatory Proteins
- Cyclohexenes
- Histone Deacetylase Inhibitors
- MCF-7 Cells
- Histone Deacetylase 6
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2020
- Paginierung
- 105076
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Datum der Datenerfassung
- 2020
- Titel
- Inhibition of cell migration and induction of apoptosis by a novel class II histone deacetylase inhibitor, MCC2344.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 160
Datenquelle: Europe PubMed Central
- 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 1162 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.
- Date of acceptance
- 2020
- Autoren
- Mona Dawood
- Edmond Fleischer
- Anette Klinger
- Gerhard Bringmann
- Letian Shan
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/32659428
- DOI
- 10.1016/j.phrs.2020.105076
- eISSN
- 1096-1186
- Zeitschrift
- Pharmacol Res
- Schlüsselwörter
- Drug development
- Epigenetics
- Leukemia
- Microscale thermophoresis
- Targeted chemotherapy
- Virtual drug screening
- Zebrafish
- Acetylation
- Animals
- Antineoplastic Agents
- Apoptosis
- Apoptosis Regulatory Proteins
- Cell Movement
- Cyclohexenes
- Epigenesis, Genetic
- HSP90 Heat-Shock Proteins
- Histone Deacetylase 6
- Histone Deacetylase Inhibitors
- Humans
- MCF-7 Cells
- Microtubules
- Neoplasm Invasiveness
- Neoplasms
- Tubulin
- Xenograft Model Antitumor Assays
- Zebrafish
- Sprache
- eng
- Country
- Netherlands
- Paginierung
- 105076
- PII
- S1043-6618(20)31384-0
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2021
- Titel
- Inhibition of cell migration and induction of apoptosis by a novel class II histone deacetylase inhibitor, MCC2344.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 160
Datenquelle: PubMed
- Beziehungen:
- Eigentum von