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Sensitizing Hypermethylator Breast Cancer Cells to Chemotherapeutics using Demethylating Agents
Author(s) -
Sandhu Rupninder,
Risher J. Devon,
Coleman William B.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.898.19
Subject(s) - demethylating agent , breast cancer , medicine , chemotherapy , oncology , pharmacology , cancer research , cancer , chemistry , dna methylation , biochemistry , gene expression , gene
Basal epithelial breast cancers express a hypermethylation defect characterized by silencing of numerous genes due to DNMT3b overexpression. This feature of basal breast cancers may account for their poor response to chemotherapy and poor long‐term survival. Using an in vitro model, we examined differences in the chemotherapeutic efficacy of doxorubicin hydrochloride (dox) against breast cancer cells depending on their methylation status. Hypermethylator breast cancer cell lines with various levels of DNMT3b (MDA‐MB‐453, BT20, and SUM102) were exposed to demethylating agents before treatment with dox. Demethylating treatment significantly increases the effectiveness of cytotoxic drugs, reducing the dose required for desired therapeutic effect. The dose of dox required to achieve 50% cell kill (IC50) is reduced by 30–35% after 3 days demethylating treatment and 60–65% after 7 days of treatment. These results indicate that: (i) demethylating treatment sensitizes hypermethylator cell lines to effects of chemotherapeutics, (ii) sensitivity is a function of the duration of exposure to demethylating drugs, and (iii) the effectiveness of demethylating treatment depends on the levels of DNMT3b activity in each cell line. These results strongly suggest that the efficacy of breast cancer chemotherapy can be improved by combination treatment with demethylating drugs.