Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Medulloblastoma is the most common brain tumor in children, and its prognosis is worse than for many other common pediatric cancers. Survivors undergoing treatment suffer from serious therapy-related side effects. Thus, it is imperative to identify safer, effective treatments for medulloblastoma. In this study we evaluated the anti-cancer potential of curcumin in medulloblastoma by testing its ability to induce apoptosis and inhibit tumor growth <it>in vitro </it>and <it>in vivo </it>using established medulloblastoma models.</p> <p>Methods</p> <p>Using cultured medulloblastoma cells, tumor xenografts, and the Smo/Smo transgenic medulloblastoma mouse model, the antitumor effects of curcumin were tested <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p>Curcumin induced apoptosis and cell cycle arrest at the G2/M phase in medulloblastoma cells. These effects were accompanied by reduced histone deacetylase (HDAC) 4 expression and activity and increased tubulin acetylation, ultimately leading to mitotic catastrophe. In <it>in vivo </it>medulloblastoma xenografts, curcumin reduced tumor growth and significantly increased survival in the Smo/Smo transgenic medulloblastoma mouse model.</p> <p>Conclusions</p> <p>The <it>in vitro </it>and <it>in vivo </it>data suggest that curcumin has the potential to be developed as a therapeutic agent for medulloblastoma.</p

Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches

Background & Hypothesis: The parasitic protozoa from the order Trypanosomatida relies exclusively on glycolysis for its survival in the mammalian hosts. As a corollary, the enzymes in this pathway have been recognised as chemotherapeutic targets. Phosphoglycerate mutase (iPGAM), which is the seventh enzyme in the pathway, is of particular interest because it possesses no structural and biochemical relationship with the corresponding enzyme in human. This enzyme has also been validated as an attractive therapeutic target for the treatment of trypanosomatid diseases. The aim of this work is to identify small molecules or compounds that could potentially be developed into potent inhibitors of trypanosomatid iPGAMs through in silico approaches. Methods: In the search for novel inhibitors, a ligand-based virtual screening programme, Ultra Fast Shape Recognition with Atom Types (UFSRAT), was utilised to screen for compounds resembling the substrate/product of iPGAM (3-phosphoglycerate/2phosphoglycerate), before a structure-based approach was applied using AutoDock Vina and COmbining Docking And Similarity Search (CODASS) programmes. The inhibitory effects of selected compounds were subsequently tested by monitoring the oxidation of nicotinamide adenine dinucleotide (NADH) through a continuous coupled assay system. Results: The results revealed that out of this collection of compounds, 7 compounds inhibited iPGAM's activity, with 1 compound from virtual screening analysis exhibited substantial inhibition (14% remaining activity). Discussion & Conclusion: Taken together, the findings from this study indicate that compounds which were discovered through in silico approaches have potentials to be developed as novel drugs that specifically target trypanosomatid iPGAMs