PMID- 19789328
OWN - NLM
STAT- MEDLINE
DCOM- 20091222
LR  - 20211020
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 15
IP  - 19
DP  - 2009 Oct 1
TI  - Identification of a novel small molecule HIF-1alpha translation inhibitor.
PG  - 6128-36
LID - 10.1158/1078-0432.CCR-08-3180 [doi]
AB  - PURPOSE: Hypoxia inducible factor-1 (HIF-1), the central mediator of the cellular 
      response to low oxygen, functions as a transcription factor for a broad range of 
      genes that provide adaptive responses to oxygen deprivation. HIF-1 is 
      overexpressed in cancer and has become an important therapeutic target in solid 
      tumors. In this study, a novel HIF-1alpha inhibitor was identified and its 
      molecular mechanism was investigated. EXPERIMENTAL DESIGN: Using a HIF-responsive 
      reporter cell-based assay, a 10,000-member natural product-like chemical compound 
      library was screened to identify novel HIF-1 inhibitors. This led us to discover 
      KC7F2, a lead compound with a central structure of cystamine. The effects of 
      KC7F2 on HIF-1 transcription, translation, and protein degradation processes were 
      analyzed. RESULTS: KC7F2 markedly inhibited HIF-mediated transcription in cells 
      derived from different tumor types, including glioma, breast, and prostate 
      cancers, and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevented the 
      activation of HIF-target genes such as carbonic anhydrase IX, matrix 
      metalloproteinase 2 (MMP2), endothelin 1, and enolase 1. An investigation into 
      the mechanism of action of KC7F2 showed that it worked through the 
      down-regulation of HIF-1alpha protein synthesis, an effect accompanied by the 
      suppression of the phosphorylation of eukaryotic translation initiation factor 4E 
      binding protein 1 and p70 S6 kinase, key regulators of HIF-1alpha protein 
      synthesis. CONCLUSION: These results show that KC7F2 is a potent HIF-1 pathway 
      inhibitor and its potential as a cancer therapy agent warrants further study.
FAU - Narita, Takuhito
AU  - Narita T
AD  - Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Winship 
      Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
FAU - Yin, Shaoman
AU  - Yin S
FAU - Gelin, Christine F
AU  - Gelin CF
FAU - Moreno, Carlos S
AU  - Moreno CS
FAU - Yepes, Manuel
AU  - Yepes M
FAU - Nicolaou, K C
AU  - Nicolaou KC
FAU - Van Meir, Erwin G
AU  - Van Meir EG
LA  - eng
GR  - R01 CA086335/CA/NCI NIH HHS/United States
GR  - CA116804/CA/NCI NIH HHS/United States
GR  - R01 CA116804-02/CA/NCI NIH HHS/United States
GR  - CA86335/CA/NCI NIH HHS/United States
GR  - R01 CA116804/CA/NCI NIH HHS/United States
GR  - R01 CA046446-13/CA/NCI NIH HHS/United States
GR  - R01 CA086335-08/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090929
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Disulfides)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (KC7F2 compound)
RN  - 0 (Small Molecule Libraries)
RN  - 0 (Sulfonamides)
RN  - S88TT14065 (Oxygen)
SB  - IM
CIN - Clin Cancer Res. 2009 Oct 1;15(19):5945-6. PMID: 19789327
MH  - Animals
MH  - Antineoplastic Agents/*isolation & purification/pharmacology/*therapeutic use
MH  - Cell Hypoxia/drug effects/physiology
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Disulfides/isolation & purification/pharmacology/therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor/methods
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolism
MH  - Mice
MH  - Models, Biological
MH  - Neoplasms/*drug therapy/pathology
MH  - Oxygen/pharmacology
MH  - Protein Biosynthesis/*drug effects
MH  - Protein Processing, Post-Translational/drug effects
MH  - Small Molecule Libraries/analysis
MH  - Sulfonamides/isolation & purification/pharmacology/therapeutic use
PMC - PMC2770235
MID - NIHMS140291
EDAT- 2009/10/01 06:00
MHDA- 2009/12/23 06:00
PMCR- 2010/10/01
CRDT- 2009/10/01 06:00
PHST- 2009/10/01 06:00 [entrez]
PHST- 2009/10/01 06:00 [pubmed]
PHST- 2009/12/23 06:00 [medline]
PHST- 2010/10/01 00:00 [pmc-release]
AID - 1078-0432.CCR-08-3180 [pii]
AID - 10.1158/1078-0432.CCR-08-3180 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2009 Oct 1;15(19):6128-36. doi: 10.1158/1078-0432.CCR-08-3180. 
      Epub 2009 Sep 29.