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).
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.
Saiko
Philipp
P
Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Graser
Geraldine
G
Giessrigl
Benedikt
B
Lackner
Andreas
A
Grusch
Michael
M
Krupitza
Georg
G
Basu
Arijit
A
Sinha
Barij Nayan
BN
Jayaprakash
Venkatesan
V
Jaeger
Walter
W
Fritzer-Szekeres
Monika
M
Szekeres
Thomas
T
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
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