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Targeted and Pharmacologic Inhibition of DNMT3b Sensitizes MDA‐MB‐453 Breast Cancer Cells to Doxorubicin and Paclitaxel
Author(s) -
Sandhu Rupninder,
Rivenbark Ashley G,
Coleman William B
Publication year - 2010
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.24.1_supplement.354.8
Subject(s) - paclitaxel , doxorubicin , gene knockdown , chemistry , chemotherapy , dnmt3b , doxorubicin hydrochloride , demethylating agent , breast cancer , cancer research , pharmacology , medicine , cancer , methyltransferase , methylation , dna methylation , apoptosis , biochemistry , gene , gene expression
Basal‐like breast cancers frequently express a hypermethylation defect characterized by DNMT hyperactivity and DNMT3b overexpression, which may contribute to chemotherapy resistance and provides a target for development of new treatment strategies. To determine the effect of DNMT3b status on the sensitivity of hypermethylator MDA‐MB‐453 breast cancer cells to doxorubicin hydrochloride (DOX) and paclitaxel (PAX), we employed RNAi‐mediated DNMT3b knockdown (KD) and/or demethylating agent treatment with 5‐aza‐2′‐deoxycytidine (5‐aza). DNMT3b KD reduces the IC 50 for DOX from 0.079 μM to 0.048 μM (39% reduction) and for PAX from 0.497 nM to 0.376 nM (24%). Treatment with 250 nM 5‐aza for 7d did not increase efficacy of DOX or PAX, but 7d treatment with 500 nM 5‐aza sensitized cells, reducing the IC 50 for DOX to 0.0349 μM (56%) and the PAX to 0.311 nM (37%). 5‐aza treatment of KD cells reduced the IC 50 for DOX to 0.0355 μM (55%) and for PAX to 0.313 nM (37%). Inhibition of DNMT3b produced improved cell killing in response to 0.079 μM DOX and 0.497 nM PAX: DNMT3b KD (19% and 10% respectively), 5‐aza (38% and 18%), and combined KD and 5‐aza treatment (39% and 18%). These results show that effectiveness of DOX and PAX can be increased by targeted and pharmacological inhibition of DNMT3b. These results strongly suggest that DNMT3b can be targeted to improve the efficacy of breast cancer chemotherapy. UNC University Cancer Research Fund