title: Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1α interaction with cofactors p300/CBP.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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-1α/HIF-1β/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-1α or other components of the HIF transcriptional complex; rather, it antagonized hypoxia-inducible transcription by disrupting the interaction of HIF-1α 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.
authors.affiliation: Departments of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, 30322, USA.
authors.forename: Shaoman
authors.initials: S
authors.lastname: Yin
authors.forename: Stefan
authors.initials: S
authors.lastname: Kaluz
authors.forename: Narra S
authors.initials: NS
authors.lastname: Devi
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Jabbar
authors.forename: Rita G
authors.initials: RG
authors.lastname: de Noronha
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Mun
authors.forename: Zhaobin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Purushotham R
authors.initials: PR
authors.lastname: Boreddy
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Abbruscato
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Olson
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011485:Protein Binding / Q000187:drug effects; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D049410:Luciferases, Renilla; D013449:Sulfonamides; C575894:3,4-dimethoxy-N-((2,2-dimethyl-2H-chromen-6-yl)methyl)-N-phenylbenzenesulfonamide; D000096926:Benzenesulfonamides; C497442:HIF1A protein, human; C494360:EP300 protein, human