Hypoxia-inducible factor stabilizers

Hypoxia creates conditions that, on one hand, are conducive to the accumulation of extracellular adenosine and, on the other hand, stabilize hypoxia-inducible factors, such as HIF-1 a (Linden 2001 Sitkovsky et al. 2004 Fredholm 2003 Hockel and Vaupel 2001 Minchenko et al. 2002 Semenza 2000). HIF-1, the most important factor involved in the cellular response to hypoxia, has been extensively studied this last decade. However, despite the substantial number of investigations into HIF-1, many secrets about its function remain to be revealed. 

Page EL, Chan DA, Giaccia AJ, Levine M, Richard DE. Hypoxia-inducible factor-la stabilization in nonhypoxic condi- 111. tions role of oxidation and intracellular ascorbate depletion. Mol. 

Koivunen P, Hirsila M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J. Inhibition of hypoxia-inducible factor (HIE) hydroxylases by citric acid cycle intermediates possible links 116. between cell metabolism and stabilization of HIE. J. Biol. Chem. 2007 282 4524-4532. 

Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT. Reactive oxygen species generated at mitochondrial complex m stabilize hypoxia-inducible factor-lalpha during hypoxia a mechanism of O2 sensing. J. Biol. Chem. 2000 275 25130-25138. 

Katschinski DM, Le L, Schindler SG, Thomas T, Voss AK, Wenger RH. Interaction of the PAS B domain with HSP90 accelerates hypoxia-inducible factor-1 alpha stabilization. Cell. Physiol. Biochem. 2004 14 351-360. 

Salceda S and Caro J (1997) Hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272 22642-22647... 

Two oxygen-sensing mechanisms help cells respond to oxygen deprivation one mechanism activates transcription of hypoxia-induced factor 1 (HIF-1), and the other promotes stabilization of HIF-1 by inhibiting its proteasomal degradation. 

Liu XH, Kirschenbaum A, Lu M, Yao S, Dosoretz A, Holland JF, Levine AC (2002a) Prostaglandin E2 induces hypoxia-inducible factor-lalpha stabilization and nuclear localization in a human prostate cancer cell line. J Biol Chem 277 50081-50086... 

Piccoli C, D Aprile A, Ripoli M, Scrima R, Boffoli D, Tabilio A, Capitanio N. The hypoxia-inducible factor is stabilized in circulating hematopoietic stem cells under normoxic conditions. FEBS Lett 2007 581 3111-3119. 

HSCs need hypoxic niche to proted them from oxidative stress because reactive oxygen spedes induce p38-MAPK-mediated proliferation leading to HSC exhaustion [105]. Some CSCs may also be concealed in hypoxic microenvironments, which are common in solid tumors. Given that hypoxia seems to be important in maintaining CSCs, this provides an opportunity for tumor-selective therapy. Hypoxia-inducible factor 1 (HIF-1) is stabilized under hypoxic conditions and promotes survival of cancer cells in hypoxic niches, so several strategies to inactivate HIF-1 are currently under investigation at the preclinical level [106,107]. 

Palmer LA, Gaston B, Johns RA. Normoxic stabilization of hypoxia-inducible factor-1 expression and activity redox-dependent effect of nitrogen oxides. Mol Pharmacol 2000 58 1197-1203. 

Hypoxia-inducing factors (HIF) play a predominant role in hypoxia-induced therapy resistance (Yasuda 2008). During hypoxia, HIF-la protein expression is stabilized leading to HIF-1-mediated gene transcription (Harris 2002 Hofer et al. 2002 ... 

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