Inhibition of cell migration and induction of apoptosis by a novel class II histone deacetylase inhibitor, MCC2344

Publication type:
Journal article
Metadata:
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

Data source: Web of Science (Lite)

Other metadata sources:
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

Data source: 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

Data source: 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

Data source: PubMed

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