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

Exp Hematol. 2005 Mar;33(3):329-35. doi: 10.1016/j.exphem.2004.11.009.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Ribavirin / pharmacology
  • Ribonucleotide Reductases / antagonists & inhibitors
  • Stilbenes / pharmacology


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