The quinoxaline di-N-oxide DCQ blocks breast cancer metastasis in vitro and in vivo by targeting the hypoxia inducible factor-1 pathway

Molecular Cancer

Research

Marwan El-Sabban¹  Kazem Zibara²  Sally El-Sitt³  Khaled Ghattass³  Hala Gali-Muhtasib³  Makhluf J Haddadin⁴  Saide Rayes⁴ 

[1] Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon;Department of Biology, Doctoral School of Science and Technology, Lebanese University, Beirut, Lebanon;Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon;Department of Chemistry, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon;

关键词: Breast cancer;    Hypoxia;    Metastasis;    HIF-1α;    DCQ;   

DOI  :  10.1186/1476-4598-13-12

 received in 2013-07-16, accepted in 2014-01-07,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAlthough tumor hypoxia poses challenges against conventional cancer treatments, it provides a therapeutic target for hypoxia-activated drugs. Here, we studied the effect of the hypoxia-activated synthetic quinoxaline di-N-oxide DCQ against breast cancer metastasis and identified the underlying mechanisms.MethodsThe human breast cancer cell lines MCF-7 (p53 wildtype) and MDA-MB-231 (p53 mutant) were treated with DCQ under normoxia or hypoxia. Drug toxicity on non-cancerous MCF-10A breast cells was also determined. In vitro cellular responses were investigated by flow cytometry, transfection, western blotting, ELISA and migration assays. The anti-metastatic effect of DCQ was validated in the MDA-MB-231 xenograft mouse model.ResultsDCQ selectively induced apoptosis in both human breast cancer cells preferentially under hypoxia without affecting the viability of non-cancerous MCF-10A. Cancer cell death was associated with an increase in reactive oxygen species (ROS) independently of p53 and was inhibited by antioxidants. DCQ-induced ROS was associated with DNA damage, the downregulation of hypoxia inducible factor-1 alpha (HIF-1α), and inhibition of vascular endothelial growth factor (VEGF) secretion. In MCF-7, HIF-1α inhibition was partially via p53-activation and was accompanied by a decrease in p-mTOR protein, suggesting interference with HIF-1α translation. In MDA-MB-231, DCQ reduced HIF-1α through proteasomal-dependent degradation mechanisms. HIF-1α inhibition by DCQ blocked VEGF secretion and invasion in MCF-7 and led to the inhibition of TWIST in MDA-MB-231. Consistently, DCQ exhibited robust antitumor activity in MDA-MB-231 breast cancer mouse xenografts, enhanced animal survival, and reduced metastatic dissemination to lungs and liver.ConclusionDCQ is the first hypoxia-activated drug showing anti-metastatic effects against breast cancer, suggesting its potential use for breast cancer therapy.

【 授权许可】

Unknown   
© Ghattass et al.; licensee BioMed Central Ltd. 2014. 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.