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Resveratrol (3,4’,5-trihydroxy-stilbene, RV), a phytoalexin present mainly in the skin of grapes and red wine, has recently attracted public and scientific attention due to its excellent radical scavenging and antitumor effects in a multitude of human cancer cell lines. The polyphenolic structure of RV is believed to contribute to these beneficial effects. In order to further enhance these qualities, our group synthesized a novel, hexahydroxy substituted derivative of RV, 3,3‘,4,4′,5,5′-hexaxydroxystilbene (M8). In the present study, we analyzed the antineoplastic and biochemical effects of M8 in comparison to RV in HL-60 human promyelocytic leukemia cells. Using growth inhibition assays, M8 proved to be more potent than RV. The two compounds yielded IC50 values of 6.25 μM versus 12 μM for M8 and RV, respectively. Using a specific Hoechst-propidium iodide double staining method, we determined the induction of apoptosis by RV and M8 in HL-60 cells and found that M8 was able to induce apoptosis at concentrations significantly lower than RV. RV has also been described as an inhibitor of ribonucleotide reductase, which is the enzyme that catalyzes the rate limiting step of de novo DNA synthesis and therefore constitutes an excellent target for cancer chemotherapy. We investigated the effects of M8 on dNTP and NTP pool sizes in HL-60 cells. Using a HPLC method, we found that M8 caused a significant increase in dCTP pools, while depleting dTTP and dATP concentrations. Upon analysis of intracellular NTP pools, M8 was able to deplete intracellular CTP, TTP, ATP and GTP concentrations and caused a significant increase in intracellular UTP pools. Moreover, we analyzed the effect of M8 on the cell cycle distribution in HL-60 cells by FACS analysis. Indeed, M8 caused a cell cycle arrest in the S phase and depleted HL-60 cells in the G0-G1 and G2-M phases. In addition, using a simultaneous growth inhibition assay, we found synergistic effects of M8 in combination with Ara-C, which is one of the first-line agents to treat acute leukemias. These results understate that M8 is a more potent cytostatic agent and inducer of apoptosis than RV and could become a valuable alternative for the treatment of hematologic malignancies.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]