Arylsulfonamide KCN1 Inhibits In Vivo Glioma Growth and Interferes with HIF Signaling by Disrupting HIF-1 alpha Interaction with Cofactors p300/CBP

作者：Yin Shaoman; Kaluz Stefan; Devi Narra S; Jabbar Adnan A; de Noronha Rita G; Mun Jiyoung; Zhang Zhaobin; Boreddy Purushotham R; Wang Wei; Wang Zhibo; Abbruscato Thomas; Chen Zhengjia; Olson Jeffrey J; Zhang Ruiwen; Goodman Mark M; Nicolaou K C; Van Meir Erwin G^*

来源：Clinical Cancer Research, 2012, 18(24): 6623-6633.

DOI：10.1158/1078-0432.CCR-12-0861

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. %26lt;br%26gt;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-1 alpha/HIF-1 beta/p300 transcription complex. %26lt;br%26gt;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-1 alpha or other components of the HIF transcriptional complex; rather, it antagonized hypoxia-inducible transcription by disrupting the interaction of HIF-1 alpha with transcriptional coactivators p300/CBP. %26lt;br%26gt;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. Clin Cancer Res; 18(24); 6623-33.

• 出版日期2012-12-15