title: Specific combinations of the chromatin-modifying enzyme modulators significantly attenuate glioblastoma cell proliferation and viability while exerting minimal effect on normal adult stem cells growth.
abstract: The discoveries of recent decade showed that all critical changes in cancer cells, such as silencing of tumor-suppressor genes and activation of oncogenes, are caused not only by genetic but also by epigenetic mechanisms. Although epigenetic changes are somatically heritable, in contrast to genetic changes, they are potentially reversible, making them good targets for therapeutic intervention. Covalent modifications of chromatin such as methylation and acetylation of histones and methylation of DNA are the important components of epigenetic machinery. In this study, we investigated the effect of different modulators of DNA and histone covalent-modifying enzymes on the proliferation and viability of normal adult stem cells, such as human bone marrow mesenchymal stem cells (hMSCs), and on malignant tumor cells, such as glioblastoma (GB) D54 cells. Results demonstrated that specific combinations of histone methyltransferases and deacetylases inhibitors significantly attenuated D54 cells viability but having only a small effect on hMSCs growth. Taken together, these studies suggest that specific combinations of histone covalent modifiers could be an effective treatment option for the most aggressive type of primary brain tumors such as glioblastoma multiforme.
authors.affiliation: Cell Reprogramming & Therapeutics LLC, W229 N1870 Westwood Drive, Waukesha, WI, 53186, USA. aalexan@cellrtherapeutics.com.
authors.forename: Arshak R
authors.initials: AR
authors.lastname: Alexanian
authors.affiliation: Department of Obstetrics and Gynecology, Medical College of Wisconsin, 9200 West Wisconsin Ave., Milwaukee, WI, 53226-3522, USA. ywhuang@mcw.edu.|Department of Pharmacology and Toxicology, Medical College of Wisconsin, 9200 West Wisconsin Ave., Milwaukee, WI, 53226-3522, USA. ywhuang@mcw.edu.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Huang
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors; D006657:Histones / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006655:Histone Deacetylases
keywords: Chromatin; DNA methylation; Epigenetic; Glioblastoma; Stem cells