PMID- 22923450
OWN - NLM
STAT- MEDLINE
DCOM- 20130528
LR  - 20211021
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 18
IP  - 24
DP  - 2012 Dec 15
TI  - Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF 
      signaling by disrupting HIF-1alpha interaction with cofactors p300/CBP.
PG  - 6623-33
LID - 10.1158/1078-0432.CCR-12-0861 [doi]
AB  - PURPOSE: The hypoxia-inducible factor-1 (HIF-1) plays a critical role in tumor 
      adaptation to hypoxia, and its elevated expression correlates with poor prognosis 
      and treatment failure in patients with cancer. In this study, we determined 
      whether 
      3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, 
      KCN1, the lead inhibitor in a novel class of arylsulfonamide inhibitors of the 
      HIF-1 pathway, had antitumorigenic properties in vivo and further defined its 
      mechanism of action. EXPERIMENTAL DESIGN: We studied the inhibitory effect of 
      systemic KCN1 delivery on the growth of human brain tumors in mice. To define 
      mechanisms of KCN1 anti-HIF activities, we examined its influence on the assembly 
      of a functional HIF-1alpha/HIF-1beta/p300 transcription complex. RESULTS: KCN1 
      specifically inhibited HIF reporter gene activity in several glioma cell lines at 
      the nanomolar level. KCN1 also downregulated transcription of endogenous HIF-1 
      target genes, such as VEGF, Glut-1, and carbonic anhydrase 9, in a 
      hypoxia-responsive element (HRE)-dependent manner. KCN1 potently inhibited the 
      growth of subcutaneous malignant glioma tumor xenografts with minimal adverse 
      effects on the host. It also induced a temporary survival benefit in an 
      intracranial model of glioma but had no effect in a model of melanoma metastasis 
      to the brain. Mechanistically, KCN1 did not downregulate the levels of HIF-1alpha or 
      other components of the HIF transcriptional complex; rather, it antagonized 
      hypoxia-inducible transcription by disrupting the interaction of HIF-1alpha with 
      transcriptional coactivators p300/CBP. CONCLUSIONS: Our results suggest that the 
      new HIF pathway inhibitor KCN1 has antitumor activity in mouse models, supporting 
      its further translation for the treatment of human tumors displaying hypoxia or 
      HIF overexpression.
CI  - (c)2012 AACR.
FAU - Yin, Shaoman
AU  - Yin S
AD  - Departments of Neurosurgery, Emory University School of Medicine, Atlanta, 
      Georgia, 30322, USA.
FAU - Kaluz, Stefan
AU  - Kaluz S
FAU - Devi, Narra S
AU  - Devi NS
FAU - Jabbar, Adnan A
AU  - Jabbar AA
FAU - de Noronha, Rita G
AU  - de Noronha RG
FAU - Mun, Jiyoung
AU  - Mun J
FAU - Zhang, Zhaobin
AU  - Zhang Z
FAU - Boreddy, Purushotham R
AU  - Boreddy PR
FAU - Wang, Wei
AU  - Wang W
FAU - Wang, Zhibo
AU  - Wang Z
FAU - Abbruscato, Thomas
AU  - Abbruscato T
FAU - Chen, Zhengjia
AU  - Chen Z
FAU - Olson, Jeffrey J
AU  - Olson JJ
FAU - Zhang, Ruiwen
AU  - Zhang R
FAU - Goodman, Mark M
AU  - Goodman MM
FAU - Nicolaou, K C
AU  - Nicolaou KC
FAU - Van Meir, Erwin G
AU  - Van Meir EG
LA  - eng
GR  - P30 CA138292/CA/NCI NIH HHS/United States
GR  - R01 CA086335/CA/NCI NIH HHS/United States
GR  - R01 CA116804/CA/NCI NIH HHS/United States
GR  - CA86335/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 - 20120824
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 
      (3,4-dimethoxy-N-((2,2-dimethyl-2H-chromen-6-yl)methyl)-N-phenylbenzenesulfonamide)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzopyrans)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Sulfonamides)
RN  - EC 1.13.12.5 (Luciferases, Renilla)
RN  - EC 2.3.1.48 (CREB-Binding Protein)
RN  - EC 2.3.1.48 (E1A-Associated p300 Protein)
RN  - EC 2.3.1.48 (EP300 protein, human)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Benzopyrans/*pharmacology
MH  - Brain Neoplasms/*drug therapy/pathology
MH  - CREB-Binding Protein/*antagonists & inhibitors/metabolism
MH  - Cell Line, Tumor
MH  - E1A-Associated p300 Protein/*antagonists & inhibitors/metabolism
MH  - Gene Expression/drug effects
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Genes, Reporter
MH  - Glioma/*drug therapy/pathology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Inhibitory Concentration 50
MH  - Luciferases, Renilla/biosynthesis/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Nude
MH  - Protein Binding/drug effects
MH  - Response Elements
MH  - Signal Transduction/drug effects
MH  - Sulfonamides/*pharmacology
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC3518680
MID - NIHMS403761
EDAT- 2012/08/28 06:00
MHDA- 2013/05/29 06:00
PMCR- 2013/12/15
CRDT- 2012/08/28 06:00
PHST- 2012/08/28 06:00 [entrez]
PHST- 2012/08/28 06:00 [pubmed]
PHST- 2013/05/29 06:00 [medline]
PHST- 2013/12/15 00:00 [pmc-release]
AID - 1078-0432.CCR-12-0861 [pii]
AID - 10.1158/1078-0432.CCR-12-0861 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2012 Dec 15;18(24):6623-33. doi: 10.1158/1078-0432.CCR-12-0861. 
      Epub 2012 Aug 24.