title: Metabolic Effects of Known and Novel HDAC and SIRT Inhibitors in Glioblastomas Independently or Combined with Temozolomide.
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.
authors.affiliation: National Research Council of Canada, 100 Rue des Aboiteaux St., Moncton, NB E1A 7R1, Canada. cuperlovim@nrc.ca.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Cuperlovic-Culf
authors.affiliation: Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada. mohamed.touaibia@umoncton.ca.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Touaibia
authors.affiliation: Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada.
authors.forename: Patrick-Denis
authors.initials: PD
authors.lastname: St-Coeur
authors.affiliation: Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada. ejp6815@umoncton.ca.
authors.forename: Julie
authors.initials: J
authors.lastname: Poitras
authors.affiliation: Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB E1A 3E9, Canada. pier.morin@umoncton.ca.
authors.forename: Pier
authors.initials: P
authors.lastname: Morin
authors.affiliation: Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada. AdrianC@canceratl.ca.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Culf