For these agents it may be hard to determine the extent HIF-1 inhibition plays in antitumor activity

For these agents it may be hard to determine the extent HIF-1 inhibition plays in antitumor activity. SMAP-2 (DT-1154) of malignancy cells, an effect that is increased in hypoxia, while non-tumor cells are less sensitive. The authors propose that KC7F2 decreases HIF-1 levels by downregulating HIF-1 protein synthesis. KC7F2 is the second HIF-1 inhibitor explained by the Van Meir group. The first, 103D5R, was reported to act similarly through inhibition of HIF-1 translation 2. Hypoxia or low oxygen tension is a feature common in all solid tumors. Tumor hypoxia is usually of major clinical significance since it can both promote tumor progression, and tumor resistance to radiation and chemotherapy. The hypoxia-inducible transcription factor (HIF), a heterodimer comprising one of two HIF- subunits (HIF-1 or HIF-2) and HIF-1, is the grasp regulator of the hypoxia response by tumors, regulating a large number SIGLEC1 of genes required for the adaptation to hypoxia. Tumor HIF-1 is usually a marker of aggressive disease and poor patient prognosis in malignancy patients. Consequently, HIF-1 has been highly ranked on the list of targets for malignancy therapy due to the important role it plays in regulating tumor survival and growth under hypoxic stress. KC7F2 joins the ranks of an increasing quantity of reported HIF-1 inhibitors whose diverse mechanisms includes the inhibition of either topoisomerase I, the Hsp90 molecular chaperone, microtubules, histone deactylases (HDACs), signaling kinases or growth factor receptors (Physique 1). That a number of these proteins are also deregulated in malignancy further validates HIF-1 as a encouraging anti-cancer target. Additionally, the fact that this modulation of a number of unrelated molecular targets ultimately result in HIF-1 inhibition through numerous mechanisms including HIF-1 synthesis, degradation or transactivation, underscores the significance of HIF-1 as a critical signaling hub, regulating cellular responses to a wide variety of stimuli. It is noteworthy that a large number of HIF-1 inhibitors appear take action at the level of translation. This highlights the significance of translation as a major pathway maintaining HIF-1 levels during hypoxia at a time when global protein translation is usually attenuated. However, the precise mechanism allowing preferential HIF-1 translation during hypoxia remains unclear. Open in a separate window Physique 1 Pathways of HIF-1 synthesis, degradation and regulation of HIF-1 activityThe HIF-1 transcription factor is usually heterodimer of HIF- and HIF-1. Under normoxic conditions HIF- undergoes quick pVHL-dependent proline hydroxylation followed by ubiquitination and proteasomal degradation. When HIF- levels increase under hypoxia it enters the nucleus to combine with HIF-1, binding to a conserved DNA sequence, the hypoxia responsive element (HRE), to transactivate a variety of hypoxia-responsive genes. Co-activators such as p300/CREB binding protein (CBP) regulate HIF-1 activity. Reported inhibitors of HIF-1 and their putative mechanism of inhibition, where known, are shown in the boxes. First generation drugs have shown that HIF-1 inhibition may provide an effective antitumor strategy. The main antitumor effect of HIF-1 inhibition appears to be through an anti-angiogenic effect mediated by the downregulation of HIF-1 downstream targets such as the vascular endothelial growth factor (VEGF). As a result, the antitumor effects of HIF-1 inhibitors SMAP-2 (DT-1154) are mostly manifested where angiogenesis is critical for continued tumor growth 3. Narita show that KC7F2 is usually SMAP-2 (DT-1154) cytotoxic to malignancy cells in normoxia when cells do not normally express HIF-1, and that KC7F2 cytotoxicity is usually potentiated by hypoxia. This suggests that although HIF-1 inhibition during hypoxia may contribute to KC7F2 cytotoxicity, the cytotoxicity under normoxia likely occurs through a separate mechanism. Further characterization of KC7F2 will show whether its HIF-1 impartial toxicity could be a potential source of unwanted side-effects. It should be noted that topotecan, a topoisomerase I inhibitor that inhibits HIF-1 translation, causes cytotoxicity by a mechanism dependent upon DNA replication-mediated DNA damage yet decreases SMAP-2 (DT-1154) HIF-1 protein levels independently of DNA damage, suggesting a mechanism of HIF-1 inhibition unique from the one responsible for the cytotoxic effects 4. Indeed, many HIF-1 inhibitors have been shown to have multiple targets which may be important for their antitumor or anti-HIF-1 activity. Additionally, many of the HIF-1 inhibitors currently in clinical SMAP-2 (DT-1154) trials have some other mechanisms of action that could also rationally account for their activity such as the inhibition of targets critical for functions including cell signaling, DNA replication and cell division. For these brokers it may be hard to determine the extent HIF-1 inhibition plays in antitumor activity. Nevertheless, some HIF-1 inhibitors accomplish their potency.

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