PMID- 21359954
OWN - NLM
STAT- MEDLINE
DCOM- 20120914
LR  - 20231213
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Linking)
VI  - 131
IP  - 2
DP  - 2012 Jan
TI  - Enhancement of chemotherapeutic efficacy in hypermethylator breast cancer cells 
      through targeted and pharmacologic inhibition of DNMT3b.
PG  - 385-99
LID - 10.1007/s10549-011-1409-2 [doi]
AB  - A subset of primary breast cancers and breast cancer cell lines express a 
      hypermethylation defect (characterized by DNMT hyperactivity and DNMT3b 
      overexpression) which contributes to chemotherapy resistance and provides a 
      target for development of new treatment strategies. The objective of the current 
      study was to determine if targeting the epigenome enhances the sensitivity of 
      breast cancer cells to cytotoxic chemotherapy. Hypermethylator breast cancer cell 
      lines (MDA-MB-453, BT549, and Hs578T) were treated with 250 or 500 nM 
      5-aza-2'-deoxycytidine (5-aza) and/or were subjected to RNAi-mediated DNMT3b 
      knockdown (KD), and then tested for sensitivity to doxorubicin hydrochloride 
      (DOX), paclitaxel (PAX), and 5-fluorouracil (5-FU). In MDA-MB-453 cells, DNMT3b 
      KD reduces the IC(50) for DOX from 0.086 to 0.048 muM (44% reduction), for PAX 
      from 0.497 to 0.376 nM (24%), and for 5-FU from 0.817 to 0.145 mM (82%). 
      Treatment with 250 nM 5-aza for 7 days did not increase the efficacy of DOX, PAX, 
      or 5-FU, but 7-day treatment with 500 nM 5-aza sensitized cells, reducing the 
      IC(50) for DOX to 0.035 muM (60%), PAX to 0.311 nM (37%), and 5-FU to 0.065 mM 
      (92%). 5-aza treatment of DNMT3b KD cells reduced the IC(50) for DOX to 0.036 muM 
      (59%), for PAX to 0.313 nM (37%) and for 5-FU to 0.067 (92%). Similar trends of 
      enhancement of cell kill were seen in BT549 (13-60%) and Hs578T (29-70%) cells 
      after RNAi-mediated DNMT3b KD and/or treatment with 5-aza. The effectiveness of 
      DOX, PAX, and 5-FU is enhanced through targeted and/or pharmacological inhibition 
      of DNMT3b, strongly suggesting that combined epigenetic and cytotoxic treatment 
      will improve the efficacy of breast cancer chemotherapy.
FAU - Sandhu, Rupninder
AU  - Sandhu R
AD  - Department of Pathology and Laboratory Medicine, University of North Carolina at 
      Chapel Hill, 515 Brinkhous Bullitt Building, CB #7525, Chapel Hill, NC 27599, 
      USA.
FAU - Rivenbark, Ashley G
AU  - Rivenbark AG
FAU - Coleman, William B
AU  - Coleman WB
LA  - eng
GR  - P30 CA016086/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110227
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0 (Antineoplastic Agents)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Breast Neoplasms/*enzymology/*genetics
MH  - Cell Line, Tumor
MH  - DNA (Cytosine-5-)-Methyltransferases/*antagonists & inhibitors/metabolism
MH  - *DNA Methylation
MH  - Drug Resistance, Neoplasm/genetics
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - RNA, Small Interfering/metabolism
MH  - DNA Methyltransferase 3B
EDAT- 2011/03/02 06:00
MHDA- 2012/09/15 06:00
CRDT- 2011/03/02 06:00
PHST- 2010/10/15 00:00 [received]
PHST- 2011/02/11 00:00 [accepted]
PHST- 2011/03/02 06:00 [entrez]
PHST- 2011/03/02 06:00 [pubmed]
PHST- 2012/09/15 06:00 [medline]
AID - 10.1007/s10549-011-1409-2 [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2012 Jan;131(2):385-99. doi: 10.1007/s10549-011-1409-2. 
      Epub 2011 Feb 27.