title: Kaempferol, a new nutrition-derived pan-inhibitor of human histone deacetylases.
abstract: Kaempferol is a natural polyphenol belonging to the group of flavonoids. Different biological functions like inhibition of oxidative stress in plants or animal cells and apoptosis induction have been directly associated with kaempferol. The underlying mechanisms are only partially understood. Here we report for the first time that kaempferol has a distinct epigenetic activity by inhibition of histone deacetylases (HDACs). In silico docking analysis revealed that it fits into the binding pocket of HDAC2, 4, 7 or 8 and thereby binds to the zinc ion of the catalytic center. Further in vitro profiling of all conserved human HDACs of class I, II and IV showed that kaempferol inhibited all tested HDACs. In clinical oncology, HDAC inhibitors are currently under investigation as new anticancer compounds. Therefore, we studied the effect of kaempferol on human-derived hepatoma cell lines HepG2 and Hep3B as well as on HCT-116 colon cancer cells and found that it induces hyperacetylation of histone complex H3. Furthermore, kaempferol mediated a prominent reduction of cell viability and proliferation rate. Interestingly, toxicity assays revealed signs of relevant cellular toxicity in primary human hepatocytes only starting at 50 μM as well as in an in vivo chicken embryotoxicity assay at 200 μM. In conclusion, the identification of a novel broad inhibitory capacity of the natural compound kaempferol for human-derived HDAC enzymes opens up the perspective for clinical application in both tumor prevention and therapy. Moreover, kaempferol may serve as a novel lead structure for chemical optimization of pharmacokinetics, pharmacology or inhibitory activities.
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Berger
authors.forename: Sascha
authors.initials: S
authors.lastname: Venturelli
authors.forename: Mascha
authors.initials: M
authors.lastname: Kallnischkies
authors.forename: Alexander
authors.initials: A
authors.lastname: Böcker
authors.forename: Christian
authors.initials: C
authors.lastname: Busch
authors.forename: Timo
authors.initials: T
authors.lastname: Weiland
authors.forename: Seema
authors.initials: S
authors.lastname: Noor
authors.forename: Christian
authors.initials: C
authors.lastname: Leischner
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Lauer
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Bischoff
authors.forename: Michael
authors.initials: M
authors.lastname: Bitzer
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002642:Chick Embryo; D003198:Computer Simulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D044949:Kaempferols / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D062105:Molecular Docking Simulation
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D044949:Kaempferols; C006552:kaempferol; D006655:Histone Deacetylases