Artikel ; Online: Synergistic anti-breast cancer effect of a combined treatment with the methyl donor S-adenosyl methionine and the DNA methylation inhibitor 5-aza-2'-deoxycytidine.
2014 Band 35, Heft 1, Seite(n) 138–144
Abstract: DNA-demethylating agents activate tumor suppressor genes that are silenced by DNA methylation in cancer and are therefore emerging as a novel approach to cancer therapy. 5-azacytidine (VIDAZA), the first representative of this class of drugs was approved ...
Abstract | DNA-demethylating agents activate tumor suppressor genes that are silenced by DNA methylation in cancer and are therefore emerging as a novel approach to cancer therapy. 5-azacytidine (VIDAZA), the first representative of this class of drugs was approved for treatment of myelodysplastic syndromes and is currently being tested on other cancers including solid tumors. However, 5-azacytidine or its deoxy-analog, 5-aza-2'-deoxycytidine (5-azaCdR) could also induce methylated prometastatic genes by DNA demethylation and induce cancer cell invasiveness. Since 5-azacytidine is a potent cancer growth inhibitor, we tested whether combining it with a DNA-methylating agent, the methyl donor S-adenosyl methionine (SAM), would block the adverse demethylating activity of 5-azaCdR while maintaining its growth suppression effects. We show here using several invasive and non-invasive breast cancer cell lines that SAM inhibits global- and gene-specific demethylation induced by 5-azaCdR, prevents 5-azaCdR activation of prometastatic genes uPA and MMP2, resulting in inhibition of cell invasiveness while augmenting the growth inhibitory effects of 5-azaCdR and its effects on tumor suppressor genes. Combination of drugs acting on the DNA methylation machinery at different levels is proposed as a new strategy for epigenetic therapy of cancer. |
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Mesh-Begriff(e) | Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Azacitidine/analogs & derivatives ; Azacitidine/pharmacology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; DNA Methylation/drug effects ; Drug Synergism ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, Tumor Suppressor ; Humans ; MCF-7 Cells/drug effects ; Matrix Metalloproteinase 2/genetics ; S-Adenosylmethionine/pharmacology ; Urokinase-Type Plasminogen Activator/genetics ; Urokinase-Type Plasminogen Activator/metabolism |
Chemische Substanzen | decitabine (776B62CQ27) ; S-Adenosylmethionine (7LP2MPO46S) ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Azacitidine (M801H13NRU) |
Sprache | Englisch |
Erscheinungsdatum | 2014-01 |
Erscheinungsland | England |
Dokumenttyp | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 603134-1 |
ISSN | 1460-2180 ; 0143-3334 |
ISSN (online) | 1460-2180 |
ISSN | 0143-3334 |
DOI | 10.1093/carcin/bgt284 |
Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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