N-hydroxy-N'-(3,4,5-trimethoxyphenyl)-3,4,5-trimethoxy-benzamidine, a novel resveratrol analog, inhibits ribonucleotide reductase in HL-60 human promyelocytic leukemia cells: Synergistic antitumor activity with arabinofuranosylcytosine

  • Authors:
    • Philipp Saiko
    • Maria Ozsvar-Kozma
    • Astrid Bernhaus
    • Margit Jaschke
    • Geraldine Graser
    • Andreas Lackner
    • Michael Grusch
    • Zsuzsanna Horvath
    • Sibylle Madlener
    • Georg Krupitza
    • Norbert Handler
    • Thomas Erker
    • Walter Jaeger
    • Monika Fritzer-Szekeres
    • Thomas Szekeres
  • View Affiliations

  • Published online on: November 1, 2007     https://doi.org/10.3892/ijo.31.5.1261
  • Pages: 1261-1266
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Abstract

Resveratrol (3,4',5,-trihydroxystilbene, RV), an ingredient of wine, exhibits a broad spectrum of antiproliferative effects against human cancer cells. In order to develop a derivative with comparable effects, we modified the molecule by introducing additional methoxyl groups. The resulting novel RV analog, N-hydroxy-N'-(3,4,5-trimethoxyphenyl)-3,4,5-trimethoxybenzamidine (KITC), was investigated in HL-60 human promyelocytic leukemia cells. The induction of apoptosis was determined employing a specific Hoechst/propidium iodide double staining method and cell cycle distribution was evaluated by FACS. KITC's influence on the concentration of deoxyribonucleoside triphosphates, the products of ribonucleotide reductase (RR), was determined using the HPLC method. In addition, we analyzed the effects of KITC treatment on the incorporation of 14C-cytidine into the DNA of tumor cells in order to quantify the loss of RR in situ activity. To reveal a potential value of KITC for supporting conventional chemotherapy, we also examined whether a combination of KITC with arabinofuranosylcytosine (Ara-C) could yield synergistic growth inhibitory effects. KITC caused a dose-dependent induction of apoptosis, whereas no remarkable changes of the cell cycle distribution were observed. Incubation with KITC resulted in a significant depletion of intracellular dTTP and dATP pools and was also found to remarkably reduce the in situ activity of RR, the key enzyme of de novo DNA synthesis. In addition, KITC exhibited synergistic combination effects when applied sequentially with Ara-C. Due to these promising results, KITC deserves further preclinical and in vivo testing.

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November 2007
Volume 31 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Saiko, P., Ozsvar-Kozma, M., Bernhaus, A., Jaschke, M., Graser, G., Lackner, A. ... Szekeres, T. (2007). N-hydroxy-N'-(3,4,5-trimethoxyphenyl)-3,4,5-trimethoxy-benzamidine, a novel resveratrol analog, inhibits ribonucleotide reductase in HL-60 human promyelocytic leukemia cells: Synergistic antitumor activity with arabinofuranosylcytosine. International Journal of Oncology, 31, 1261-1266. https://doi.org/10.3892/ijo.31.5.1261
MLA
Saiko, P., Ozsvar-Kozma, M., Bernhaus, A., Jaschke, M., Graser, G., Lackner, A., Grusch, M., Horvath, Z., Madlener, S., Krupitza, G., Handler, N., Erker, T., Jaeger, W., Fritzer-Szekeres, M., Szekeres, T."N-hydroxy-N'-(3,4,5-trimethoxyphenyl)-3,4,5-trimethoxy-benzamidine, a novel resveratrol analog, inhibits ribonucleotide reductase in HL-60 human promyelocytic leukemia cells: Synergistic antitumor activity with arabinofuranosylcytosine". International Journal of Oncology 31.5 (2007): 1261-1266.
Chicago
Saiko, P., Ozsvar-Kozma, M., Bernhaus, A., Jaschke, M., Graser, G., Lackner, A., Grusch, M., Horvath, Z., Madlener, S., Krupitza, G., Handler, N., Erker, T., Jaeger, W., Fritzer-Szekeres, M., Szekeres, T."N-hydroxy-N'-(3,4,5-trimethoxyphenyl)-3,4,5-trimethoxy-benzamidine, a novel resveratrol analog, inhibits ribonucleotide reductase in HL-60 human promyelocytic leukemia cells: Synergistic antitumor activity with arabinofuranosylcytosine". International Journal of Oncology 31, no. 5 (2007): 1261-1266. https://doi.org/10.3892/ijo.31.5.1261