Background:

Chetomin, an antibiotic metabolite of chaetomium cochliodes, is an inhibitor of HIF-1 by weaken transcription of HIF-1 and recently is raised interests as a cancer chemotherapeutic agent.[1]
HIF-1 (hypoxia-inducible factors 1) is transcription factor which respond to changes of cellular environment oxygen. [2] HIF-1 complex belongs to the PAS subfamily of the basic helix-loop-helix family of transcription factors and is composed of an alpha subunit and a beta subunit which formed a heterodimer. [3] HIF-1 can upregulate several genes such as glycolysis enzymes, vascular endothelial growth factor to promote survival rate of cells in hopoxia conditions through binding to HIF-responsive elements in the promoters. NF- Kappa B was shown a direct modulator of HIF-1alpha in normal condition but in low-oxygen conditions HIF-1alpha still stable with an unknown mechanism. [4]
Chetomin selectively inhibited HIF-1 activities through disruption of the interaction of HIF-1with its transcriptional coactivator p300. Early-passage human fibrosarcoma HT1080 cells stably transfected EGFP plasmid with a hypoxia-responsive 5HRE-hCMVmp promoter were pretreated with chetomin showed dose and incubation-time dependent EGFP fluorescence signal suppression. And pretreatment of 150nM chetomin for 4h showed maximum suppressive effects, indicated the inhibition of HIF-dependent transcription. Also, 150nM chetomin decreased expression of VEGF and CA9 under hapoxic conditions in HT1010 cells. Chetomin increased cell survival rate under hypoxia compared mormoxia conditions, indicated that chetomin can enhanced radiation treatment efficacy under severely hypoxic conditions.[5]
参考文献:
[1] Timothy R. Welch and Robert M. Williams. Studies on the Biosynthesis of Chetomin: Enantiospecific Synthesis of a Putative, Late-Stage Biosynthetic Intermediate. Tetrahedron (2013) 69(2): 770–773
[2] Smith TG, Robbins PA, Ratcliffe PJ. The human side of hypoxia-inducible factor. Br. J. Haematol. (2008)141(3): 325–34
[3] Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J. Biol. Chem. (1996) 271(30):17771-17778
[4] Van Uden P, Kenneth NS, Rocha S. Regulation of hypoxia-inducible factor-1 alpha by NF-kappa B. Biochem. J. (2008) 412(3): 477-484
[5] Adrian Staab, Jürgen Loeffler, Harun M Said, Désirée Diehlmann, Astrid Katzer, Melanie Beyer, Markus Fleischer, Franz Schwab, Kurt Baier, Hermann Einsele, Michael Flentje and Dirk Vordermark. Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma  Cells. BMC Cancer (2007) 7 :213