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Metabolites 2014, 4(3), 807-830; doi:10.3390/metabo4030807

Metabolic Effects of Known and Novel HDAC and SIRT Inhibitors in Glioblastomas Independently or Combined with Temozolomide

1
National Research Council of Canada, 100 Rue des Aboiteaux St., Moncton, NB E1A 7R1, Canada
2
Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada
3
Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
*
Author to whom correspondence should be addressed.
Received: 7 May 2014 / Revised: 20 August 2014 / Accepted: 4 September 2014 / Published: 12 September 2014
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Abstract

Inhibition of protein deacetylation enzymes, alone or in combination with standard chemotherapies, is an exciting addition to cancer therapy. We have investigated the effect of deacetylase inhibition on the metabolism of glioblastoma cells. 1H NMR metabolomics analysis was used to determine the major metabolic changes following treatment of two distinct glioblastoma cell lines, U373 and LN229, with five different histone deacetylase (HDAC) inhibitors, as well as one inhibitor of NAD+-dependent protein deacetylases (SIRT). The addition of the standard glioblastoma chemotherapy agent, temozolomide, to the HDAC and SIRT treatments led to a reduction in cell survival, suggesting a possibility for combined treatment. This study shows that distinct glioblastoma cell lines, with different metabolic profiles and gene expression, experience dissimilar changes following treatment with protein deacetylase inhibitors. The observed effects of inhibitors on mitochondrial metabolism, glycolysis and fatty acid synthesis suggest possible roles of protein deacetylases in metabolism regulation. Metabolic markers of the effectiveness of anti-protein deacetylase treatments have been explored. In addition to known deacetylation inhibitors, three novel inhibitors have been introduced and tested. Finally, 1H NMR analysis of cellular metabolism is shown to be a fast, inexpensive method for testing drug effects. View Full-Text
Keywords: metaboloepigenomics; NMR metabolomics; glioblastoma; enzyme inhibitors; combined treatment metaboloepigenomics; NMR metabolomics; glioblastoma; enzyme inhibitors; combined treatment
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Cuperlovic-Culf, M.; Touaibia, M.; St-Coeur, P.-D.; Poitras, J.; Morin, P., Jr; Culf, A.S. Metabolic Effects of Known and Novel HDAC and SIRT Inhibitors in Glioblastomas Independently or Combined with Temozolomide. Metabolites 2014, 4, 807-830.

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