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)

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• 作者：Philipp Saiko ; Geraldine Graser ; Benedikt Giessrigl ; Andreas Lackner ; Michael Grusch ; Georg Krupitza ; Arijit Basu ; Barij Nayan Sinha ; Venkatesan Jayaprakash ; Walter Jaeger ; Monika Fritzer-Szekeres ; Th
• 关键词：N-hydroxy-N′ ; -aminoguanidines ; Ribonucleotide reductase ; Cell cycle arrest ; Arabinofuranosylcytosine ; Synergistic combination effects
• 刊名：Biochemical Pharmacology
• 出版年：2011
• 出版时间：1 January 2011
• 年：2011
• 卷：81
• 期：1
• 页码：50-59
• 全文大小：492 K

文摘

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.