These results suggest that chaetocin has therapeutic potential fo

These results suggest that chaetocin has therapeutic potential for the control of solid tumors, including hepatoma. Furthermore, our findings suggest that HIF-1α pre-mRNA splicing should also be viewed as a therapeutic Ensartinib order target. The thiodioxopiperazine moiety of chaetocin has chirality opposite to that of chetomin. Chetomin has been reported to directly

inhibit the interaction between HIF-1α and p300 and, thus, to repress HIF-1-driven gene expression.21 A recent report demonstrated that despite structural differences, three thiodioxopiperazines commonly inhibit the p300 binding in vitro and reduce VEGF secretion in HCT116 cells.22 However, as HIF-1α expression had not been determined, we examined whether chetomin, like chaetocin, down-regulates HIF-1α. Although chetomin selleckchem repressed the transcriptional activity of HIF-1α, it had no effect on HIF-1α expression or pre-mRNA splicing (Supporting Information Fig. 7). These results indicate that chaetocin and chetomin inhibit HIF-1α in different ways. Indeed, we could not check the effect of chaetocin on p300-HIF-1α binding because HIF-1α disappeared. Nevertheless, because HIF-1α synthesis precedes p300-HIF-1α binding, the anticancer effect of chaetocin might be primarily

due to HIF-1α suppression. VEGF acts in a paracrine manner on endothelial cells to increase numbers of blood and lymphatic vessels, and also in an autocrine manner activates the VEGF receptor-mediated survival pathway. Therefore, antibodies

and peptides that antagonize VEGF or its receptors have been developed as anticancer therapies.23, 24 We found that chaetocin inhibits VEGF production in hepatoma cells and grafts, and that vessels were poorly developed in chaetocin-treated tumors. These results suggest that the VEGF suppression underlies the antiangiogenic and anticancer action of chaetocin. To correct ATP depletion and subsequent acidosis in hypoxia, HIF-1α facilitates ATP generation by up-regulating PDK4 a number of glycolytic enzymes, but it inhibits oxidative phosphorylation by inducing PDK1, which blocks the trichloroacetic acid (TCA) cycle.25 HIF-1α also corrects acidosis by inducing CA9, which generates HCO.26 Accordingly, suppression of these metabolic genes by chaetocin may contribute to its cytotoxicity to hepatoma cells cultured under severe hypoxic conditions. Many small molecules that inhibit HIF-1 have been reported in the literature. Some functionally inhibit HIF-1α by blocking its binding to p300 or DNA,21, 27 and others down-regulate HIF-1α by destabilizing it or by inhibiting its translation.28, 29 However, to the best of our knowledge, no agent has been previously reported to inhibit HIF-1α at the mRNA splicing level. Then, how does chaetocin inhibit HIF-1α pre-mRNA splicing? Spliceosome consists of small nuclear ribonucleoproteins and a host of associated proteins.

Leave a Reply

Your email address will not be published. Required fields are marked *

*

You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>