Potent inhibition of tumoral hypoxia-inducible factor 1α by albendazole

BMC Cancer

Research Article

Samina Badar¹  Mohammad H Pourgholami¹  David L Morris¹  Zhao Y Cai¹  Kiran Wangoo¹  Marianne S Poruchynsky² 

[1] Cancer Research laboratories, University of New South Wales Department of Surgery, St George Hospital, 2217, Sydney, NSW, Australia;Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA;

关键词: Vascular Endothelial Growth Factor;    Vascular Endothelial Growth Factor Expression;    Vascular Endothelial Growth Factor Level;    Albendazole;    Vascular Endothelial Growth Factor Protein;   

DOI  :  10.1186/1471-2407-10-143

 received in 2010-01-06, accepted in 2010-04-15,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundEmerging reports suggest resistance, increased tumor invasiveness and metastasis arising from treatment with drugs targeting vascular endothelial growth factor (VEGF). It is believed that increased tumoral hypoxia plays a prominent role in the development of these phenomena. Inhibition of tumoral hypoxia inducible factor (HIF-1α) is thus becoming an increasingly attractive therapeutic target in the treatment of cancer. We hypothesized that the anti-VEGF effect of albendazole (ABZ) could be mediated through inhibition of tumoral HIF-1α.MethodIn vitro, the effects of ABZ on HIF-1α levels in human ovarian cancer cells (OVCAR-3) were investigated using hypoxic chamber or desferrioxamine (DFO) induced-hypoxia. In vivo, the effects of ABZ (150 mg/kg, i.p., single dose) on the tumor levels of HIF-1α and VEGF protein and mRNA were investigated by western blotting, RT-PCR and real time-PCR.ResultsIn vitro, ABZ inhibited cellular HIF-1α protein accumulation resulting from placement of cells under hypoxic chamber or exposure to DFO. In vivo, tumors excised from vehicle treated mice showed high levels of both HIF-1α and VEGF. Whereas, tumoral HIF-1α and VEGF protein levels were highly suppressed in ABZ treated mice. Tumoral VEGFmRNA (but not HIF-1αmRNA) was also found to be highly suppressed by ABZ.ConclusionThese results demonstrate for the first time the effects of an acute dose of ABZ in profoundly suppressing both HIF-1α and VEGF within the tumor. This dual inhibition may provide additional value in inhibiting angiogenesis and be at least partially effective in inhibiting tumoral HIF-1α surge, tumor invasiveness and metastasis.

【 授权许可】

Unknown   
© Pourgholami et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.