ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.

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. Considering this, we hypothesized that ELR510444, a novel orally available small molecule inhibitor of HIF act...

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Main Authors: Jennifer S Carew, Juan A Esquivel, Claudia M Espitia, Christoph M Schultes, Marcel Mülbaier, Joe D Lewis, Bernd Janssen, Francis J Giles, Steffan T Nawrocki
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2012-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3266297?pdf=render
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author Jennifer S Carew
Juan A Esquivel
Claudia M Espitia
Christoph M Schultes
Marcel Mülbaier
Joe D Lewis
Bernd Janssen
Francis J Giles
Steffan T Nawrocki
author_facet Jennifer S Carew
Juan A Esquivel
Claudia M Espitia
Christoph M Schultes
Marcel Mülbaier
Joe D Lewis
Bernd Janssen
Francis J Giles
Steffan T Nawrocki
author_sort Jennifer S Carew
collection DOAJ
description 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. 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.ELR510444 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.ELR510444 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.
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spelling doaj.art-efc0859661774db09ea52cde675cc4cd2022-12-22T03:48:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0171e3112010.1371/journal.pone.0031120ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.Jennifer S CarewJuan A EsquivelClaudia M EspitiaChristoph M SchultesMarcel MülbaierJoe D LewisBernd JanssenFrancis J GilesSteffan T NawrockiHypoxia-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.ELR510444 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.ELR510444 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.http://europepmc.org/articles/PMC3266297?pdf=render
spellingShingle Jennifer S Carew
Juan A Esquivel
Claudia M Espitia
Christoph M Schultes
Marcel Mülbaier
Joe D Lewis
Bernd Janssen
Francis J Giles
Steffan T Nawrocki
ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.
PLoS ONE
title ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.
title_full ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.
title_fullStr ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.
title_full_unstemmed ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.
title_short ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma.
title_sort elr510444 inhibits tumor growth and angiogenesis by abrogating hif activity and disrupting microtubules in renal cell carcinoma
url http://europepmc.org/articles/PMC3266297?pdf=render
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