Synergistic action of resveratrol, an ingredient of wine, with Ara-C and tiazofurin in HL-60 human promyelocytic leukemia cells.

Abstract

OBJECTIVE:

Resveratrol, a naturally occurring stilbene derivative, is a potent free-radical scavenger causing a number of biochemical and antineoplastic effects. It was shown to induce differentiation and apoptosis in leukemia cells. Resveratrol was also identified as an inhibitor of ribonucleotide reductase (RR), a key enzyme of DNA synthesis. We report about the biochemical effects of resveratrol on the concentration of deoxyribonucleoside triphosphates (dNTPs), the products of RR, and on the incorporation of 14C-labeled cytidine into the DNA of HL-60 human promyelocytic leukemia cells.

MATERIALS AND METHODS:

Incorporation of 14C-labeled cytidine into the DNA of resveratrol-treated HL-60 cells was measured. Concentration of dNTPs was determined by a HPLC method. Cytotoxic effects of resveratrol, Ara-C, and tiazofurin were analyzed using growth inhibition and clonogenic assays. Induction of apoptosis was studied using a Hoechst/propidium iodide staining method.

RESULTS:

We found that resveratrol effectively inhibited incorporation of 14C-labeled cytidine into DNA. Furthermore, incubation of HL-60 cells with resveratrol significantly decreased intracellular dCTP, dTTP, dATP, and dGTP concentrations. Based on these results, we investigated the combination effects of resveratrol with Ara-C or tiazofurin, both antimetabolites, which are known to exhibit synergistic effects in combination with other inhibitors of RR. In growth inhibition, apoptosis, and clonogenic assays, resveratrol acted synergistically with both Ara-C and tiazofurin in HL-60 cells.

CONCLUSIONS:

We conclude that resveratrol could become a viable candidate as one compound in the combination chemotherapy of leukemia and therefore deserves further testing.

• Authors: Zsuzsanna Horvath, Philipp Saiko, Christoph Illmer, Sibylle Madlener, Thomas Hoechtl, Wolfgang Bauer, Thomas Erker, Walter Jaeger, Monika Fritzer-Szekeres, Thomas Szekeres
• Journal: Experimental hematology (Exp Hematol) Vol. 33 Issue 3 Pg. 329-35 (Mar 2005) ISSN: 0301-472X [Print] Netherlands
• PMID: 15730856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Deoxyribonucleotides
• Stilbenes
• Cytarabine
• Ribavirin
• DNA
• Ribonucleotide Reductases
• Resveratrol
• tiazofurin

Topics

• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• Cytarabine (pharmacology)
• DNA (biosynthesis)
• Deoxyribonucleotides (metabolism)
• Drug Synergism
• HL-60 Cells
• Humans
• Leukemia, Promyelocytic, Acute (drug therapy)
• Resveratrol
• Ribavirin (analogs & derivatives, pharmacology)
• Ribonucleotide Reductases (antagonists & inhibitors)
• Stilbenes (pharmacology)