title: A novel N-hydroxy-N'-aminoguanidine derivative inhibits ribonucleotide reductase activity: Effects in human HL-60 promyelocytic leukemia cells and synergism with arabinofuranosylcytosine (Ara-C).
abstract: Ribonucleotide reductase (RR; EC 1.17.4.1) is responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA replication. RR is upregulated in tumor cells and therefore considered to be an excellent target for cancer chemotherapy. ABNM-13 (N-hydroxy-2-(anthracene-2-yl-methylene)-hydrazinecarboximidamide), a novel N-hydroxy-N'-aminoguanidine has been designed to inhibit RR activity using 3D molecular space modeling techniques. In this study, we evaluated its effect on human HL-60 promyelocytic leukemia cells. ABNM-13 proved to be a potent inhibitor of RR which was displayed by significant alterations of deoxyribonucleoside triphosphate (dNTP) pool balance and a highly significant decrease of incorporation of radiolabeled cytidine into DNA of HL-60 cells. Diminished RR activity caused replication stress which was consistent with activation of Chk1 and Chk2, resulting in downregulation/degradation of Cdc25A. In contrast, Cdc25B was upregulated, leading to dephosphorylation and activation of Cdk1. The combined disregulation of Cdc25A and Cdc25B was the most likely cause for ABNM-13 induced S-phase arrest. Finally, we combined ABNM-13 with the first-line antileukemic agent arabinofuranosylcytosine (Ara-C) and found that ABNM-13 synergistically potentiated the antineoplastic effects of Ara-C. Due to these promising results, ABNM-13 deserves further preclinical and in vivo testing.
authors.affiliation: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Saiko
authors.forename: Geraldine
authors.initials: G
authors.lastname: Graser
authors.forename: Benedikt
authors.initials: B
authors.lastname: Giessrigl
authors.forename: Andreas
authors.initials: A
authors.lastname: Lackner
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Georg
authors.initials: G
authors.lastname: Krupitza
authors.forename: Arijit
authors.initials: A
authors.lastname: Basu
authors.forename: Barij Nayan
authors.initials: BN
authors.lastname: Sinha
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Jayaprakash
authors.forename: Walter
authors.initials: W
authors.lastname: Jaeger
authors.forename: Monika
authors.initials: M
authors.lastname: Fritzer-Szekeres
authors.forename: Thomas
authors.initials: T
authors.lastname: Szekeres
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000494:pharmacology; D008558:Melphalan / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D006146:Guanidines; D007074:Immunoglobulin G; C051713:antineoplastic agent K 18; D003561:Cytarabine; C062817:N-hydroxy-N'-aminoguanidine; D012264:Ribonucleotide Reductases; D008558:Melphalan