Arylsulfonamide KCN1 InhibitsIn VivoGlioma Growth and Interferes with HIF Signaling by Disrupting HIF-1α Interaction with Cofactors p300/CBP

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.

Human Brat Ortholog TRIM3 Is a Tumor Suppressor That Regulates Asymmetric Cell Division in Glioblastoma

“…Cell proliferation was analyzed at 0, 24, 48, 72, 96, and 168h by Sulforhodamine B assay (Sigma-Aldrich) [29]. …”

Overcoming therapeutic resistance in glioblastoma: the way forward

“…Microenvironmental changes such as hypoxia can also render tumors more resistant to conventional therapies. Hypoxic cells display increased radiation resistance because oxygen radicals play a major role in the damage generated by irradiation and because hypoxia-inducible transcription factor (HIF) alters the DNA damage response (145)(146)(147). Cytotoxic chemotherapies delivered via the bloodstream diffuse into the tumors from functional blood vessels, and the hypoxic areas are the furthest removed from these vessels.…”

A Negative Feedback of the HIF-1α Pathway via Interferon-Stimulated Gene 15 and ISGylation

“…Several regulatory mechanisms affecting the activity of HIF-1a have been identified: (i) HIF-1a stability is regulated by changes in oxygen tension. HIF-1a is degraded under normoxia by UPP, which involves prolyl hydroxylase (PHD1/2/3)-mediated hydroxylation and VHL-mediated ubiquitinylation (3,15); (ii) Factor inhibiting HIF-1 (FIH) hydroxylates HIF-1a on Asp 803, leading to blockages of the recruitment of the p300/CBP coactivator and subsequent transcription inactivation (16,17); (iii) HIF-1a functions as a transcription factor in a heterodimeric form composed of two subunits, HIF-1a and HIF-1b (18); (iv) HIF-1a protein expression depends on both cap-and IRES-directed translation (19,20); (v) IFN-t, one of the Type I IFN produced only in ruminants and/or progesterone regulate HIF mRNA expression in the ovine endometrium and sheep conceptuses (21,22). Cytokines and growth factors could stimulate HIF-1a protein synthesis and that cytokines induce the NF-kB-dependent expression of HIF-1a mRNA under hypoxia (23).…”