Inhibition of Hypoxia Inducible Factor-2 Transcription: Isolation of Active Modulators from Marine Sponges

Abstract

Renal or kidney cancer accounts for about 3% of all cancer cases reported each year in the US. Molecular signatures that define the cancer, such as the loss of functional VHL, are found in both sporadic and familial cases of cancer. In clear cell renal cancer, the transcription factor HIF-2α has been shown to have a distinct role in tumorigenesis. Our laboratories developed a cell-based screen to identify modulators of HIF-2α. Screening of the NCI’s Natural Product Extract Repository resulted in the identification of 10 sponge extracts from which 12 compounds were isolated. The biological evaluation of these compounds will be discussed including evaluation of HIF-1α vs. HIF-2αselectively and the isolated compounds’ effects on mRNA from several pathways regulated by HIF.

Prognostic Role of Hypoxic Inducible Factor Expression in Non-small Cell Lung Cancer: A Meta-analysis

“…Despite the more prominent role in neovascularization, it regulates hypoxia-regulated genes such as c-Myc and p53, similarly to HIF1, but differs in detailed mechanism (Uchida et al, 2004). Previous in vitro and in vivo data implicating HIF-2α as an important pro-tumor factor is abundant with no controversy (Jackson et al, 2010;McKee et al, 2012).…”

“…In addition, HIF-2α also gradually comes into people's sight as a considerable therapeutic target. McKee et al (2012) and his partners tried to separate and identify small molecule inhibitors of HIF-2 gene expression through a high throughput screen (HTS), but the final compounds they identified are only discussed in vitro evaluation so that further development need to be conducted. Our data can provide a more sufficient evidence to ensure practical value of HIF inhibitors and promote relevant industries especially of HIF2.…”

Marine Compounds and Cancer

“…Most fatty acids are considered PPARs agonist; nevertheless DHA suppresses its activation. This statement was demonstrated by Lee and Hwang (2002) [146] in colon tumor cells (HCT116).…”

“…Cancer preventive compounds may stimulate anticancer immunity, inhibit inflammation, angiogenesis and tumor invasion, or protect from UV-radiation damage [144][145][146][147]. Preincubation with mytilan, a polysaccharide isolated from the mussel Crenomytilus grayanus, was followed by a normalization of the activity indicators of human peripheral blood lymphocytes and by a reduction of the number of morphological defects of the marine invertebrates larvae after UV-irradiation [148].…”

“…Five HDAC1 inhibitors, trichostatin A (126, Figure 30 Ten extracts from various marine sponges were identified as containing inhibitors of the transcription factor HIF-2 which has been shown to play a distinct role in tumorigenesis. Chemical exploration of these sponge extracts led to isolation of seven specific HIF inhibitors, compounds 131-136 ( Figure 31) and haliclonadiamine (62) [146]. Gliotoxin-related compounds 144-147 ( Figure 33), containing a disulfide or tetrasulfide bond, were isolated from the fungus Penicillium sp.…”