The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function.
Br J Cancer
; 106(10): 1638-47, 2012 May 08.
Article
em En
| MEDLINE
| ID: mdl-22498643
ABSTRACT
BACKGROUND:
Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule HIF-pathway inhibitor NSC-134754.METHODS:
Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought.RESULTS:
In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c-Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC-134754-treated tumours revealed lower expression of HIF-1α and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment.CONCLUSION:
NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator 1 Induzível por Hipóxia
/
Isoquinolinas
/
Antineoplásicos
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Br J Cancer
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Reino Unido