title: Geranylated flavanone tomentodiplacone B inhibits proliferation of human monocytic leukaemia (THP-1) cells.
abstract: OBJECTIVE
  Paulownia tomentosa is a rich source of geranylated flavanones, some of which we have previously shown to have cytotoxic activity. To identify members of this class of compounds with cytostatic effects, we assessed the effects of the geranylated flavanone tomentodiplacone B (TOM B) on cell cycle progression and cell cycle regulatory pathways of THP-1 human monocytic leukaemia cells.
  
  
  METHODS
  Cell viability was measured by dye exclusion and proliferation by WST-1 assays; cell cycle was monitored by flow cytometry. Regulatory proteins were assessed by immunoprecipitation and kinase assays, and Western blotting.
  
  
  RESULTS
  Tomentodiplacone B had no effect during the first 24 h of cell growth at concentrations between 1 and 2.5 µM, but inhibited cell growth in a dose-dependent manner at concentrations of 5 µM or higher. Growth inhibition during the first 24 h of exposure to TOM B was not accompanied by cytotoxicity as cells were accumulated in G1 phase dose-dependently. This G1 phase accumulation was associated with down-regulation of cyclin-dependent kinase 2 activity and also protein levels of cyclins E1 and A2. However, key stress-related molecules (γ-H2AX, p53 and p21) were not induced, suggesting that TOM B acts by directly inhibiting the cyclin-dependent kinase 2 signalling pathway rather than initiating DNA damage or cellular stress.
  
  
  CONCLUSIONS
  Our study provides the first evidence that TOM B directly inhibits proliferation of human monocytic leukaemia cells, and thus is a potential anticancer agent, preventing leukaemia cells from progressing from G1 phase into DNA synthesis.
authors.affiliation: Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic. kollarp@vfu.cz
authors.forename: Peter
authors.initials: P
authors.lastname: Kollár
authors.forename: Tomáš
authors.initials: T
authors.lastname: Bárta
authors.forename: Veronika
authors.initials: V
authors.lastname: Závalová
authors.forename: Karel
authors.initials: K
authors.lastname: Smejkal
authors.forename: Aleš
authors.initials: A
authors.lastname: Hampl
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056741:Cyclin D / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D044950:Flavanones / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007948:Leukemia, Monocytic, Acute; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D056741:Cyclin D; D016213:Cyclins; D044950:Flavanones; D039821:Monoterpenes; C559286:tomentodiplacone B; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2