Abstract
BackgroundHypoxia-inducible factor (HIF) is an attractive therapeutic target for renal cell carcinoma (RCC) as its high expression due to the loss of von Hippel-Lindau (VHL) promotes RCC progression. Considering this, we hypothesized that ELR510444, a novel orally available small molecule inhibitor of HIF activity, would reduce angiogenesis and possess significant activity in RCC. The mechanism of action and therapeutic efficacy of ELR510444 were investigated in in vitro and in vivo models of RCC.Principal FindingsELR510444 decreased HIF-1α and HIF-2α levels, reduced RCC cell viability and clonogenic survival, and induced apoptosis. VHL-deficient RCC cells were more sensitive to ELR510444-mediated apoptosis and restoration of VHL promoted drug resistance. Higher concentrations of ELR51044 promoted apoptosis independently of VHL status, possibly due to the microtubule destabilizing properties of this agent. ELR510444 significantly reduced tumor burden in the 786-O and A498 RCC xenograft models. These effects were associated with increased necrosis and apoptosis and inhibition of angiogenesis.ConclusionsELR510444 is a promising new HIF inhibitor that reduced RCC cell viability, induced apoptosis, and diminished tumor burden in RCC xenograft models. ELR510444 also destabilized microtubules suggesting that it possesses vascular disrupting and anti-angiogenic properties. Further investigation of ELR510444 for the therapy of RCC is warranted.
Highlights
Overexpression of the hypoxia inducible factors (HIFs) Hypoxia-inducible factor (HIF)-1a or HIF-2a is associated with cancer progression [1,2,3,4,5,6]
Antibodies and reagents Antibodies were obtained from the following commercial sources: anti-VEGF (Santa Cruz Biotechnology, Santa Cruz, CA); anti-HIF-1a (R&D Systems, Minneapolis, MN); anti-HIF-2a (Novus Biologicals, Littleton, CO); anti-cleaved caspase-3 (Cell Signaling, Danvers, MA); anti-b-tubulin (Sigma-Aldrich, St Louis, MO); anti-CD31 (BD Pharmingen, San Jose, CA); anti-proliferating cell nuclear antigen (PCNA) (Dako, Glostrup, Denmark); goat anti-rabbit and goat anti-rat horseradish peroxidase (HRP)conjugated secondary antibodies (Jackson Laboratories, West Grove, PA); Rat anti-mouse IgG2a-HRP (Serotec, Raleigh, NC); Goat anti-mouse Alexa Fluor 488 and 49,6-diamidino-2-phenylindole (DAPI) (Invitrogen, Carlsbad, CA); and sheep anti-mouseHRP and donkey anti-rabbit-HRP (Amersham, Pittsburgh, PA)
ELR510444 reduces the expression of HIF-1a, HIF-2a, and VEGF in renal cell carcinoma (RCC) cells
Summary
Overexpression of the hypoxia inducible factors (HIFs) HIF-1a or HIF-2a is associated with cancer progression [1,2,3,4,5,6]. The consequential upregulation of HIFs promote the increased expression of genes involved in angiogenesis (vascular endothelial growth factor, VEGF), metabolism (Glut-1), drug resistance (MDR-1), and cell survival (Bcl-2) [8,9,10]. Hypoxia-inducible factor (HIF) is an attractive therapeutic target for renal cell carcinoma (RCC) as its high expression due to the loss of von Hippel-Lindau (VHL) promotes RCC progression. The mechanism of action and therapeutic efficacy of ELR510444 were investigated in in vitro and in vivo models of RCC
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