Cellular physiology and biochemistry, 2018-11, Vol.51 (2), p.543-556
2018
Details
- Autor(en) / Beteiligte
- Titel
- 6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells
- Ist Teil von
- Cellular physiology and biochemistry, 2018-11, Vol.51 (2), p.543-556
- Ort / Verlag
- Basel, Switzerland: S. Karger AG
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- The Electronic Journals Library
- Beschreibungen/Notizen
- Background/Aims: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). Methods: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells. Results: In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 µmol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. Conclusion: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1015-8987eISSN: 1421-9778DOI: 10.1159/000495275Titel-ID: cdi_crossref_primary_10_1159_000495275
- Format
- –
- Schlagworte
- 6-PN, 6-prenylnaringenin, 8-PN, 8-prenylnaringenin, Acetylation - drug effects, Apoptosis, Apoptosis - drug effects, Binding Sites, Catalytic Domain, Cell Line, Tumor, Cell Proliferation - drug effects, Down-Regulation - drug effects, Epigenetics, Extracellular Signal-Regulated MAP Kinases - metabolism, Flavanones - chemistry, Flavanones - isolation & purification, Flavanones - pharmacology, Flavonoids - chemistry, Flavonoids - isolation & purification, Flavonoids - pharmacology, HDAC, Histone deacetalyse inhibition, Histone Deacetylase Inhibitors - chemistry, Histone Deacetylase Inhibitors - isolation & purification, Histone Deacetylase Inhibitors - pharmacology, Histone Deacetylases - chemistry, Histone Deacetylases - metabolism, Histones - metabolism, Hops, Humans, Humulus - chemistry, Humulus - metabolism, Kinases, Melanoma, Melanoma - metabolism, Melanoma - pathology, Molecular Docking Simulation, Mutation, Original Paper, Protein Isoforms - antagonists & inhibitors, Protein Isoforms - metabolism, Ribosomal Protein S6 Kinases - genetics, Ribosomal Protein S6 Kinases - metabolism, Therapy, TOR Serine-Threonine Kinases - metabolism