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
| Autor: | Flora Chik, Moshe Szyf, Ziv Machnes |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
S-Adenosylmethionine Azacitidine Breast Neoplasms Biology Decitabine chemistry.chemical_compound Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Humans Genes Tumor Suppressor S-Adenosyl methionine Epigenetics Cancer Drug Synergism General Medicine DNA Methylation medicine.disease Urokinase-Type Plasminogen Activator Gene Expression Regulation Neoplastic DNA demethylation chemistry Cancer cell DNA methylation Cancer research MCF-7 Cells Matrix Metalloproteinase 2 Female Epigenetic therapy medicine.drug |
| Zdroj: | Carcinogenesis. 35(1) |
| ISSN: | 1460-2180 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|