Artelastin, a novel prenylated
flavone, previously isolated from the wood bark of Artocarpus elasticus, was evaluated for its capacity to inhibit the growth of fifty-two human tumor cell lines, representing nine different
tumor types. A pronounced dose-dependent growth inhibitory effect was detected in all the cell lines, with GI50 values ranging from 0.8-20.8 microM. Studies to elucidate the basis of the growth inhibitory activity of
artelastin were performed in the MCF-7 human
breast cancer cell line (GI50 = 6.0 microM). We show that
artelastin exerts a biphasic effect in the
DNA synthesis of MCF-7 cells, a stimulatory effect at low concentrations (below GI50) for short times of exposition (6 h and 24 h), and an inhibitory effect at high concentrations (above GI50). Remarkably, treated cells that have
DNA synthesis affected could be viable and metabolically active. Furthermore,
artelastin acts as a cytotoxic rather than a
cytostatic compound. Massive cytoplasmatic vacuoles were detected in cells after
artelastin treatment. Together with these morphological alterations, cells show the presence of abnormal nuclear morphologies, and occasionally nuclear condensation, which were identified as apoptotic by TUNEL assay. Moreover,
artelastin was shown to disturb the microtubule network while no effect was observed on the kinetochores. Flow cytometry analysis of cells treated with
artelastin reveal an accumulation in S phase that interferes with the cell cycle progression. Additionally, according to
BrdU patterns, studies with synchronized cells at G0 and at G1/S transition also suggest that
artelastin delays DNA replication since progression of cells trough S-phase is perturbed.