title: Cytotoxic and biochemical effects of 3,3',4,4',5,5'-hexahydroxystilbene, a novel resveratrol analog in HL-60 human promyelocytic leukemia cells.
abstract: OBJECTIVE
  Resveratrol (3,4',5,-trihydroxystilbene, RV), an ingredient of wine, is an inhibitor of the proliferation-linked enzyme ribonucleotide reductase (RR) and shows a broad spectrum of cytotoxic effects against human cancer cells. In order to enhance these effects, we introduced additional hydroxyl moieties into the molecule. In the present study, the activity of a novel RV analog, 3,3',4,4',5,5'-hexahydroxystilbene (M8), was investigated in HL-60 human promyelocytic leukemia cells.
  
  
  METHODS
  Cytotoxicity of M8 alone or in combination with Ara-C was assessed employing growth inhibition assays. Effects of M8 on nucleoside triphosphates (NTPs) and deoxynucleoside triphosphates (dNTPs) were examined by HPLC. The apoptotic potential of M8 and RV was compared using a specific double-staining method and inhibition of TNF-alpha-induced activation of NF-kappaB was studied. Cell-cycle distribution was analyzed by FACS.
  
  
  RESULTS
  Addition of ascorbic acid decreased the IC(50) value of M8 from 6.25 microM to 2 microM. M8 depleted dATP and dTTP pools to 41% and 21% of control values, whereas dCTP pools increased to 199% of untreated controls. In addition, TTP, ATP, CTP, and GTP concentrations were decreased while UTP concentrations increased. M8 induced apoptosis at concentrations significantly lower than RV and could remarkably inhibit the activation of NF-kappaB. M8 arrested cells in the S phase of the cell cycle while depleting cells in the G2-M phase and exhibited synergistic combination effects when applied simultaneously with Ara-C.
  
  
  CONCLUSIONS
  Due to these promising results, this novel polyhydroxylated stilbene derivative might become an additional option for the treatment of leukemia and therefore deserves further preclinical and in vivo testing.
authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Horvath
authors.forename: Marek
authors.initials: M
authors.lastname: Murias
authors.forename: Philipp
authors.initials: P
authors.lastname: Saiko
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Norbert
authors.initials: N
authors.lastname: Handler
authors.forename: Sibylle
authors.initials: S
authors.lastname: Madlener
authors.forename: Walter
authors.initials: W
authors.lastname: Jaeger
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Monika
authors.initials: M
authors.lastname: Fritzer-Szekeres
authors.forename: Georg
authors.initials: G
authors.lastname: Krupitza
authors.forename: Thomas
authors.initials: T
authors.lastname: Szekeres
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology; D003854:Deoxyribonucleotides / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D011748:Pyrogallol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077185:Resveratrol; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D012265:Ribonucleotides / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014920:Wine
chemical_list: C514772:3,3',4,4',5,5'-hexahydroxystilbene; D003854:Deoxyribonucleotides; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D012265:Ribonucleotides; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D011748:Pyrogallol; D003561:Cytarabine; D012264:Ribonucleotide Reductases; D000077185:Resveratrol