PMID- 18645011
OWN - NLM
STAT- MEDLINE
DCOM- 20080908
LR  - 20211020
IS  - 1535-7163 (Print)
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 7
IP  - 7
DP  - 2008 Jul
TI  - Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic 
      cancer cell growth and migration.
PG  - 2012-21
LID - 10.1158/1535-7163.MCT-08-0113 [doi]
AB  - AP endonuclease 1 (APE1; also known as REF-1) contains a DNA repair domain and a 
      redox regulation domain. APE1 is overexpressed in several human cancers, and 
      disruption of APE1 function has detrimental effects on cancer cell viability. 
      However, the selective contribution of the redox and the DNA repair domains to 
      maintenance of cellular homeostasis in cancer has not been elucidated. In the 
      present study, we used E3330, a small-molecule inhibitor of APE1 redox domain 
      function, to interrogate the functional relevance of sustained redox function in 
      pancreatic cancer. We show that E3330 significantly reduces the growth of human 
      pancreatic cancer cells in vitro. This phenomenon was further confirmed by a 
      small interfering RNA experiment to knockdown APE1 expression in pancreatic 
      cancer cells. Further, the growth-inhibitory effects of E3330 are accentuated by 
      hypoxia, and this is accompanied by striking inhibition in the DNA-binding 
      ability of hypoxia-inducible factor-1alpha, a hypoxia-induced transcription 
      factor. E3330 exposure promotes endogenous reactive oxygen species formation in 
      pancreatic cancer cells, and the resulting oxidative stress is associated with 
      higher levels of oxidized, and hence inactive, SHP-2, an essential protein 
      tyrosine phosphatase that promotes cancer cell proliferation in its active state. 
      Finally, E3330 treatment inhibits pancreatic cancer cell migration as assessed by 
      in vitro chemokine assays. E3330 shows anticancer properties at multiple 
      functional levels in pancreatic cancer, such as inhibition of cancer cell growth 
      and migration. Inhibition of the APE1 redox function through pharmacologic means 
      has the potential to become a promising therapeutic strategy in this disease.
FAU - Zou, Gang-Ming
AU  - Zou GM
AD  - Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns 
      Hopkins University School of Medicine, 1550 Orleans Street, CRB-2, M341, 
      Baltimore, MD 21231, USA. gzou1@jhmi.edu
FAU - Maitra, Anirban
AU  - Maitra A
LA  - eng
GR  - P30 CA006973/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Benzoquinones)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hyaluronan Receptors)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Propionates)
RN  - 0 (Reactive Oxygen Species)
RN  - 136164-66-4 (E 3330)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
RN  - EC 4.2.99.18 (APEX1 protein, human)
RN  - EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase)
SB  - IM
MH  - Benzoquinones/*pharmacology
MH  - Cell Hypoxia/drug effects
MH  - Cell Line, Tumor
MH  - Cell Movement/*drug effects
MH  - Cell Proliferation/drug effects
MH  - Chemokine CXCL12/metabolism
MH  - DNA, Neoplasm/metabolism
MH  - DNA-(Apurinic or Apyrimidinic Site) Lyase/*antagonists & inhibitors
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/*pharmacology
MH  - Epithelial Cells/drug effects/pathology
MH  - G1 Phase/drug effects
MH  - G2 Phase/drug effects
MH  - Humans
MH  - Hyaluronan Receptors/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Models, Biological
MH  - Oxidation-Reduction/drug effects
MH  - Pancreas/pathology
MH  - Pancreatic Neoplasms/*enzymology/*pathology
MH  - Propionates/*pharmacology
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
MH  - Reactive Oxygen Species/metabolism
PMC - PMC3569736
MID - NIHMS436971
EDAT- 2008/07/23 09:00
MHDA- 2008/09/09 09:00
PMCR- 2013/02/12
CRDT- 2008/07/23 09:00
PHST- 2008/07/23 09:00 [pubmed]
PHST- 2008/09/09 09:00 [medline]
PHST- 2008/07/23 09:00 [entrez]
PHST- 2013/02/12 00:00 [pmc-release]
AID - 7/7/2012 [pii]
AID - 10.1158/1535-7163.MCT-08-0113 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2008 Jul;7(7):2012-21. doi: 10.1158/1535-7163.MCT-08-0113.