Vitamin K3 chloro derivative (VKT-2) inhibits HDAC6, activates autophagy and apoptosis, and inhibits aggresome formation in hepatocellular carcinoma cells
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Mona Dawood
- Mohamed-Elamir F Hegazy
- Mohamed Elbadawi
- Edmond Fleischer
- Anette Klinger
- Gerhard Bringmann
- Claudia Kuntner
- Letian Shan
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000579310000062&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.bcp.2020.114176
- eISSN
- 1873-2968
- Externe Identifier
- Clarivate Analytics Document Solution ID: OC7BF
- PubMed Identifier: 32721508
- ISSN
- 0006-2952
- Zeitschrift
- BIOCHEMICAL PHARMACOLOGY
- Schlüsselwörter
- Drug development
- Epigenetics
- Vitamin K-3
- HDAC6
- Zebrafish
- Artikelnummer
- ARTN 114176
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Titel
- Vitamin K<sub>3</sub> chloro derivative (VKT-2) inhibits HDAC6, activates autophagy and apoptosis, and inhibits aggresome formation in hepatocellular carcinoma cells
- Sub types
- Article
- Ausgabe der Zeitschrift
- 180
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Mona Dawood
- Mohamed-Elamir F Hegazy
- Mohamed Elbadawi
- Edmond Fleischer
- Anette Klinger
- Gerhard Bringmann
- Claudia Kuntner
- Letian Shan
- Thomas Efferth
- DOI
- 10.1016/j.bcp.2020.114176
- ISSN
- 0006-2952
- Zeitschrift
- Biochemical Pharmacology
- Sprache
- en
- Artikelnummer
- 114176
- Paginierung
- 114176 - 114176
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.bcp.2020.114176
- Datum der Datenerfassung
- 2022
- Titel
- Vitamin K3 chloro derivative (VKT-2) inhibits HDAC6, activates autophagy and apoptosis, and inhibits aggresome formation in hepatocellular carcinoma cells
- Ausgabe der Zeitschrift
- 180
Data source: Crossref
- Abstract
- Epigenetics plays a vital role in regulating gene expression and determining the specific phenotypes of eukaryotic cells. Histone deacetylases (HDACs) are important epigenetic regulatory proteins effecting multiple biological functions. Particularly, HDAC6 has become a promising anti-cancer drug target because of its regulation of cell mobility, protein trafficking, degradation of misfolded proteins, cell growth, apoptosis, and metastasis. In this study, we identified one out of six vitamin K<sub>3</sub> derivatives, VKT-2, as HDAC6 inhibitor using molecular docking and cell viability assays in HDAC6-overexpressing HuH-7 cancer cells. Microscale thermophoresis and HDAC6 enzymatic assays revealed that VKT-2 bound to HDAC6 and inhibited its function. We further identified its cytotoxic activity. VKT-2 hyperacetylated HDAC6 substrates and disturbed tubulin integrity leading to significant inhibition of tumor migration in both HuH-7 spheroids and U2OS-GFP-α-tubulin cells. Moreover, VKT-2 induced autophagic and apoptotic cell death in HuH-7, while aggresome formation was restrained after VKT-2 treatment. A HuH-7 cell-xenograft model in zebrafish larvae provided evidence that VKT-2 inhibited the tumor growth in vivo. To best of our knowledge, it is the first time to demonstrate that vitamin k<sub>3</sub> derivatives (VKT-2) inhibits HDAC6 in solid tumor cells. These unique findings suggested that VKT-2 is a promising anti-cancer agent targeting HDAC6.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany; Department of Molecular Biology, Faculty of Medical Laboratory Science, Al-Neelain University, Khartoum, Sudan.
- Autoren
- Mona Dawood
- Mohamed-Elamir F Hegazy
- Mohamed Elbadawi
- Edmond Fleischer
- Anette Klinger
- Gerhard Bringmann
- Claudia Kuntner
- Letian Shan
- Thomas Efferth
- DOI
- 10.1016/j.bcp.2020.114176
- eISSN
- 1873-2968
- Externe Identifier
- PubMed Identifier: 32721508
- Funding acknowledgements
- Alexander von Humboldt Foundation:
- Ministry of Higher Education and Scientific Research and of the Al-Neelain University, Khartoum, Sudan:
- International Office, Johannes Gutenberg University:
- Open access
- false
- ISSN
- 0006-2952
- Zeitschrift
- Biochemical pharmacology
- Schlüsselwörter
- HCT116 Cells
- Animals
- Zebrafish
- Humans
- Carcinoma, Hepatocellular
- Liver Neoplasms
- Vitamin K 3
- Xenograft Model Antitumor Assays
- Apoptosis
- Cell Aggregation
- Cell Survival
- Dose-Response Relationship, Drug
- Autophagy
- Histone Deacetylase Inhibitors
- HEK293 Cells
- MCF-7 Cells
- Histone Deacetylase 6
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2020
- Paginierung
- 114176
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Datum der Datenerfassung
- 2020
- Titel
- Vitamin K<sub>3</sub> chloro derivative (VKT-2) inhibits HDAC6, activates autophagy and apoptosis, and inhibits aggresome formation in hepatocellular carcinoma cells.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 180
Data source: Europe PubMed Central
- Abstract
- Epigenetics plays a vital role in regulating gene expression and determining the specific phenotypes of eukaryotic cells. Histone deacetylases (HDACs) are important epigenetic regulatory proteins effecting multiple biological functions. Particularly, HDAC6 has become a promising anti-cancer drug target because of its regulation of cell mobility, protein trafficking, degradation of misfolded proteins, cell growth, apoptosis, and metastasis. In this study, we identified one out of six vitamin K3 derivatives, VKT-2, as HDAC6 inhibitor using molecular docking and cell viability assays in HDAC6-overexpressing HuH-7 cancer cells. Microscale thermophoresis and HDAC6 enzymatic assays revealed that VKT-2 bound to HDAC6 and inhibited its function. We further identified its cytotoxic activity. VKT-2 hyperacetylated HDAC6 substrates and disturbed tubulin integrity leading to significant inhibition of tumor migration in both HuH-7 spheroids and U2OS-GFP-α-tubulin cells. Moreover, VKT-2 induced autophagic and apoptotic cell death in HuH-7, while aggresome formation was restrained after VKT-2 treatment. A HuH-7 cell-xenograft model in zebrafish larvae provided evidence that VKT-2 inhibited the tumor growth in vivo. To best of our knowledge, it is the first time to demonstrate that vitamin k3 derivatives (VKT-2) inhibits HDAC6 in solid tumor cells. These unique findings suggested that VKT-2 is a promising anti-cancer agent targeting HDAC6.
- Date of acceptance
- 2020
- Autoren
- Mona Dawood
- Mohamed-Elamir F Hegazy
- Mohamed Elbadawi
- Edmond Fleischer
- Anette Klinger
- Gerhard Bringmann
- Claudia Kuntner
- Letian Shan
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/32721508
- DOI
- 10.1016/j.bcp.2020.114176
- eISSN
- 1873-2968
- Zeitschrift
- Biochem Pharmacol
- Schlüsselwörter
- Drug development
- Epigenetics
- HDAC6
- Vitamin K(3)
- Zebrafish
- Animals
- Apoptosis
- Autophagy
- Carcinoma, Hepatocellular
- Cell Aggregation
- Cell Survival
- Dose-Response Relationship, Drug
- HCT116 Cells
- HEK293 Cells
- Histone Deacetylase 6
- Histone Deacetylase Inhibitors
- Humans
- Liver Neoplasms
- MCF-7 Cells
- Vitamin K 3
- Xenograft Model Antitumor Assays
- Zebrafish
- Sprache
- eng
- Country
- England
- Paginierung
- 114176
- PII
- S0006-2952(20)30412-3
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2020
- Titel
- Vitamin K3 chloro derivative (VKT-2) inhibits HDAC6, activates autophagy and apoptosis, and inhibits aggresome formation in hepatocellular carcinoma cells.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 180
Data source: PubMed
- Beziehungen:
- Property of