[Proc Amer Assoc Cancer Res, Volume 47, 2006]
Experimental and Molecular Therapeutics 39: Novel Antitumor Agents 4
Biochemical effects of Piceatannol in human HL-60 promyelocytic leukemia cells - synergism with Ara-C
Walter Jaeger and
Medical University of Vienna, Vienna, Austria and University of Vienna, Vienna, Austria
Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene; PT) is a naturally occurring metabolite of Resveratrol (RV). It possesses extensive cytostatic activity, triggers apoptosis, inhibits cellular pathways associated with cell proliferation, and causes cell cycle arrest in various tumor cell lines, such as human leukemia or melanoma cell lines. Due to the presence of multiple hydroxyl groups, these compounds are excellent antioxidants and effective free radical scavengers, a fact that is responsible for the anticancer effects of stilbene derivatives. PT was indeed demonstrated to be a potent inducer of apoptosis in various tumor cells, such as colon, melanoma, lymphoma or leukemia cell lines and to inhibit tyrosine kinase activity in malignant cells. In this study, we attempted to identify additional biochemical targets of PT in human HL-60 promyelocytic leukemia cells. One of these targets is ribonucleotide reductase (RR, EC 126.96.36.199
), which is the rate limiting enzyme of de novo DNA synthesis with relatively low activity in resting normal cells and significantly elevated enzyme activity in malignant tumor cells. The enzyme is therefore considered to be another excellent target for cancer chemotherapy. After incubation of cells with increasing concentrations of PT for 72 hours, an IC50 value (50% growth inhibition in comparison with untreated control cells) of 14 µM could be observed. Incubation with 40µM PT led to significant proportions of apoptotic cells (95%) and caused an arrest in the G2-M phase while depleting cells in the S phase of the cell cycle. PT was also shown to deplete intracellular dCTP and dGTP pools, and to effectively inhibit the incorporation of 14C-labeled cytidine into DNA, thus inhibiting RR in situ activity. Moreover, treatment with 40µM or 80µM PT significantly depleted all NTP pools. Employing a sequential growth inhibition assay, treatment with PT and Ara-C yielded synergistic combination indices for 8 out of 12 concentrations applied (according to the equations of Chou and Talalay). We conclude that the use of PT might become an additional option for the combination treatment of leukemia and other human malignancies. Based on our data, further studies using this agent alone or in combination with Ara-C are warranted.
Copyright © 2006 by the American Association for Cancer Research.