Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1? interaction with co-factors p300/CBP

• Type of Material: Article
• Authors: Shaoman Yin, Emory University; Stefan Kaluz, Emory University; Narra S. Devi, Emory University; Adnan A. Jabbar, Emory University; Rita G. de Noronha, The Scripps Research Institute; Jiyoung Mun, Emory University; Zhaobin Zhang, Emory University; Purushotham R. Boreddy, Texas Tech University; Wei Wang, Texas Tech University Health Sciences Center; Zhibo Wang, Emory University; Thomas Abbruscato, Texas Tech University; Zhengjia Chen, Emory University; Jeffrey James Olson, Emory University; Ruiwen Zhang, Texas Tech University Health Sciences Center; Mark Goodman, Emory University; K.C. Nicolaou, The Scripps Research Institute; Erwin Van Meir, Emory University
• Language: English
• Date: 2012-12-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Association for Cancer Research.
• Final Published Version (URL): http://clincancerres.aacrjournals.org/content/18/24/6623
• Title of Journal or Parent Work: Clinical Cancer Research
• ISSN: 1078-0432
• Volume: 18
• Issue: 24
• Start Page: 6623
• End Page: 6633
• Grant/Funding Information: This work was supported in part by the American Brain Tumor Association, the Charlotte Geyer Foundation, EmTechBio, the Southeastern Brain Tumor Foundation, the Emory University Research Council, the NIH (R01 CA116804, CA86335 and P30 CA138292), the V Foundation, the Max Cure Foundation and the Samuel Waxman Cancer Research Foundation.
• Research Categories: Health Sciences, Oncology; Health Sciences, General

Abstract

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 cancer patients. 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 anti-tumorigenic 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 HIF1α/HIF1β/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 an 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 down-regulate 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 co-activators 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.