title: Epigallocatechin gallate, ellagic acid, and rosmarinic acid perturb dNTP pools and inhibit de novo DNA synthesis and proliferation of human HL-60 promyelocytic leukemia cells: Synergism with arabinofuranosylcytosine.
abstract: Epigallocatechin gallate (EGCG), ellagic acid (EA) and rosmarinic acid (RA) are natural polyphenols exerting cancer chemopreventive effects. Ribonucleotide reductase (RR; EC 1.17.4.1) converts ribonucleoside diphosphates into deoxyribonucleoside diphosphates being essential for DNA replication, which is why the enzyme is considered an excellent target for anticancer therapy. EGCG, EA, and RA dose-dependently inhibited the growth of human HL-60 promyelocytic leukemia cells, exerted strong free radical scavenging potential, and significantly imbalanced nuclear deoxyribonucleoside triphosphate (dNTP) concentrations without distinctly affecting the protein levels of RR subunits (R1, R2, p53R2). Incorporation of (14)C-cytidine into nascent DNA of tumor cells was also significantly lowered, being equivalent to an inhibition of DNA synthesis. Consequently, treatment with EGCG and RA attenuated cells in the G0/G1 phase of the cell cycle, finally resulting in a pronounced induction of apoptosis. Sequential combination of EA and RA with the first-line antileukemic agent arabinofuranosylcytosine (AraC) synergistically potentiated the antiproliferative effect of AraC, whereas EGCG plus AraC yielded additive effects. Taken together, we show for the first time that EGCG, EA, and RA perturbed dNTP levels and inhibited cell proliferation in human HL-60 promyelocytic leukemia cells, with EGCG and RA causing a pronounced induction of apoptosis. Due to these effects and synergism with AraC, these food ingredients deserve further preclinical and in vivo testing as inhibitors of leukemic cell proliferation.
authors: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Philipp
authors: P
authors: Saiko
authors: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Marie-Thérèse
authors: MT
authors: Steinmann
authors: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Heike
authors: H
authors: Schuster
authors: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Geraldine
authors: G
authors: Graser
authors: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Sabine
authors: S
authors: Bressler
authors: Department of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Benedikt
authors: B
authors: Giessrigl
authors: Department of Medicine I, Division of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors: Andreas
authors: A
authors: Lackner
authors: Department of Medicine I, Division of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors: Michael
authors: M
authors: Grusch
authors: Department of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Georg
authors: G
authors: Krupitza
authors: Department of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Zsuzsanna
authors: Z
authors: Bago-Horvath
authors: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors: Walter
authors: W
authors: Jaeger
authors: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Monika
authors: M
authors: Fritzer-Szekeres
authors: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Electronic address: thomas.szekeres@meduniwien.ac.at.
authors: Thomas
authors: T
authors: Szekeres
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D053630:Depsides / Q000494:pharmacology*; D004357:Drug Synergism; D004610:Ellagic Acid / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D013942:Thymine Nucleotides / Q000737:chemistry; D000097123:Rosmarinic Acid
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D002392:Catechin; D002934:Cinnamates; D003561:Cytarabine; D004247:DNA; D053630:Depsides; D004610:Ellagic Acid; D016166:Free Radical Scavengers; D019384:Nucleic Acid Synthesis Inhibitors; D013942:Thymine Nucleotides; D000097123:Rosmarinic Acid; C045651:epigallocatechin gallate
keywords: Arabinofuranosylcytosine; Ellagic acid; Epigallocatechin gallate; HL-60 cells; Ribonucleotide reductase; Rosmarinic acid