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Biomap#27

Title: List of HIF-1 alpha inhibitors
 
Legend: Hypoxia-inducible factor (HIF) is a transcription factor found in mammalian cells cultured under reduced oxygen tension and plays a key role in the cellular response to hypoxia. HIF is a heterodimer consisting of two subunits, the oxygen-sensitive HIF-alpha (with three homologues: HIF-1 alpha [the most studied], HIF-2 alpha and HIF-3 alpha) and the constitutively expressed HIF-beta. In normoxia, HIF-alpha is targeted by the tumor suppressor VHL (the recognition component of an E3 ubiquitin ligase complex), which leads to HIF-alpha ubiquitylation and consequent proteasomal degradation. In hypoxia, HIF-alpha is stabilized and its levels increase. Then, HIF-alpha translocates from the cytoplasm to the nucleus where it dimerizes with HIF-beta and promotes the transcription of some 40 genes, most of which encode angiogenesis and cell survival related proteins. HIF-1 alpha overexpression can be found in many tumor types (including melanoma) and has been reported to correlate with patient prognosis. Moreover, preclinical tumor models suggest that HIF-1 alpha inhibition can have therapeutic potential. Several molecules (e.g. ARC-111, sodium butyrate, trichostatin-A, bortezomib, NSC644221, chrysin, vitexin, nelfinavir, NPV-LAQ824, noscapine, L-NMMA, echinomycin, lonafarnib, polyamide-1, 103D5R, pseudolaric acid B, SN38, PX-478, berberine, NS398, chetomin) have been found to inhibit HIF-1 alpha expression/activity and thus are under investigation as anticancer agents. REFERENCES: [1] Patiar S et al, Endocr Relat Cancer 2006, 13:S61-75. [2] Belozerov VE et al, Curr Opin Investig Drugs 2006, 7:1067-76
Author: The MMMP Team (updated: Nov 2007)

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