A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Xiaohua Lu
- Ge Yan
- Mona Dawood
- Sabine M Klauck
- Yoshikazu Sugimoto
- Anette Klinger
- Edmond Fleischer
- Letian Shan
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000729042500006&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.bcp.2021.114677
- eISSN
- 1873-2968
- Externe Identifier
- Clarivate Analytics Document Solution ID: XM8AK
- PubMed Identifier: 34265280
- ISSN
- 0006-2952
- Zeitschrift
- BIOCHEMICAL PHARMACOLOGY
- Schlüsselwörter
- Apoptosis
- Histone deacetylases
- Leukemia
- Multidrug resistance
- P-glycoprotein
- Zebrafish
- Artikelnummer
- ARTN 114677
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Titel
- A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells
- Sub types
- Article
- Ausgabe der Zeitschrift
- 194
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Xiaohua Lu
- Ge Yan
- Mona Dawood
- Sabine M Klauck
- Yoshikazu Sugimoto
- Anette Klinger
- Edmond Fleischer
- Letian Shan
- Thomas Efferth
- DOI
- 10.1016/j.bcp.2021.114677
- ISSN
- 0006-2952
- Zeitschrift
- Biochemical Pharmacology
- Sprache
- en
- Artikelnummer
- 114677
- Paginierung
- 114677 - 114677
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.bcp.2021.114677
- Datum der Datenerfassung
- 2022
- Titel
- A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells
- Ausgabe der Zeitschrift
- 194
Data source: Crossref
- Abstract
- New and potent agents that evade multidrug resistance (MDR) and inhibit epigenetic modifications are of great interest in cancer drug development. Here, we describe that a moniliformin derivative (IUPAC name: 3-(naphthalen-2-ylsulfanyl)-4-{[(2Z)-1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene]methyl}cyclobut-3-ene-1,2-dione; code: MCC1381) bypasses P-gp-mediated MDR. Using transcriptomics, we identified a large number of genes significantly regulated in response to MCC1381, which affected the cell cycle and disturbed cellular death and survival. The potential targets of MCC1381 might be histone deacetylases (HDACs) as predicted by SwissTargetPrediction. In silico studies confirmed that MCC1381 presented comparable affinity with HDAC1, 2, 3, 6, 8 and 11. Besides, the inhibition activity of HDACs was dose-dependently inhibited by MCC1381. Particularly, a strong binding affinity was observed between MCC1381 and HDAC6 by microscale thermophoresis analysis. MCC1381 decreased the expression of HDAC6, inversely correlated with the increase of acetylated HDAC6 substrates, acetylation p53 and α-tubulin. Furthermore, MCC1381 arrested the cell cycle at the G<sub>2</sub>/M phase, induced the generation of reactive oxygen species and collapse of the mitochondrial membrane potential. MCC1381 exhibited in vivo anti-cancer activity in xenografted zebrafish. Collectively, MCC1381 extended cytotoxicity towards P-gp-resistant leukemia cancer cells and may act as a pan-HDACs inhibitor, indicating that MCC1381 is a novel candidate for cancer therapy.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
- Autoren
- Xiaohua Lu
- Ge Yan
- Mona Dawood
- Sabine M Klauck
- Yoshikazu Sugimoto
- Anette Klinger
- Edmond Fleischer
- Letian Shan
- Thomas Efferth
- DOI
- 10.1016/j.bcp.2021.114677
- eISSN
- 1873-2968
- Externe Identifier
- PubMed Identifier: 34265280
- Open access
- false
- ISSN
- 0006-2952
- Zeitschrift
- Biochemical pharmacology
- Schlüsselwörter
- HCT116 Cells
- Animals
- Zebrafish
- Humans
- Leukemia
- Cyclobutanes
- Histone Deacetylases
- Mycotoxins
- Xenograft Model Antitumor Assays
- Apoptosis
- Cell Survival
- Protein Structure, Secondary
- Protein Structure, Tertiary
- Dose-Response Relationship, Drug
- Histone Deacetylase Inhibitors
- HEK293 Cells
- Molecular Docking Simulation
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2021
- Paginierung
- 114677
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum der Datenerfassung
- 2021
- Titel
- A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 194
Data source: Europe PubMed Central
- Abstract
- New and potent agents that evade multidrug resistance (MDR) and inhibit epigenetic modifications are of great interest in cancer drug development. Here, we describe that a moniliformin derivative (IUPAC name: 3-(naphthalen-2-ylsulfanyl)-4-{[(2Z)-1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene]methyl}cyclobut-3-ene-1,2-dione; code: MCC1381) bypasses P-gp-mediated MDR. Using transcriptomics, we identified a large number of genes significantly regulated in response to MCC1381, which affected the cell cycle and disturbed cellular death and survival. The potential targets of MCC1381 might be histone deacetylases (HDACs) as predicted by SwissTargetPrediction. In silico studies confirmed that MCC1381 presented comparable affinity with HDAC1, 2, 3, 6, 8 and 11. Besides, the inhibition activity of HDACs was dose-dependently inhibited by MCC1381. Particularly, a strong binding affinity was observed between MCC1381 and HDAC6 by microscale thermophoresis analysis. MCC1381 decreased the expression of HDAC6, inversely correlated with the increase of acetylated HDAC6 substrates, acetylation p53 and α-tubulin. Furthermore, MCC1381 arrested the cell cycle at the G2/M phase, induced the generation of reactive oxygen species and collapse of the mitochondrial membrane potential. MCC1381 exhibited in vivo anti-cancer activity in xenografted zebrafish. Collectively, MCC1381 extended cytotoxicity towards P-gp-resistant leukemia cancer cells and may act as a pan-HDACs inhibitor, indicating that MCC1381 is a novel candidate for cancer therapy.
- Date of acceptance
- 2021
- Autoren
- Xiaohua Lu
- Ge Yan
- Mona Dawood
- Sabine M Klauck
- Yoshikazu Sugimoto
- Anette Klinger
- Edmond Fleischer
- Letian Shan
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/34265280
- DOI
- 10.1016/j.bcp.2021.114677
- eISSN
- 1873-2968
- Zeitschrift
- Biochem Pharmacol
- Schlüsselwörter
- Apoptosis
- Histone deacetylases
- Leukemia
- Multidrug resistance
- P-glycoprotein
- Zebrafish
- Animals
- Apoptosis
- Cell Survival
- Cyclobutanes
- Dose-Response Relationship, Drug
- HCT116 Cells
- HEK293 Cells
- Histone Deacetylase Inhibitors
- Histone Deacetylases
- Humans
- Leukemia
- Molecular Docking Simulation
- Mycotoxins
- Protein Structure, Secondary
- Protein Structure, Tertiary
- Xenograft Model Antitumor Assays
- Zebrafish
- Sprache
- eng
- Country
- England
- Paginierung
- 114677
- PII
- S0006-2952(21)00290-2
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2022
- Titel
- A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 194
Data source: PubMed
- Beziehungen:
- Property of