Although 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.
Methods:
The 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.
Results:
DCQ 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-1alpha), and inhibition of vascular endothelial growth factor (VEGF) secretion. In MCF-7, HIF-1alpha inhibition was partially via p53-activation and was accompanied by a decrease in p-mTOR protein, suggesting interference with HIF-1alpha translation.
In MDA-MB-231, DCQ reduced HIF-1alpha through proteasomal-dependent degradation mechanisms. HIF-1alpha 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.
Conclusion:
DCQ is the first hypoxia-activated drug showing anti-metastatic effects against breast cancer, suggesting its potential use for breast cancer therapy.
Author: Khaled GhattassSally El-SittKazem ZibaraSaide RayesMakhluf J HaddadinMarwan El-SabbanHala Gali-Muhtasib
Credits/Source: Molecular Cancer 2014, 13:12
Published on: 2014-01-24
Tweet
News Provider: EUPB – European Press Bureau
Social Bookmarking
RETWEET This! | Digg this! | Post to del.icio.us | Post to Furl | Add to Netscape | Add to Yahoo! | Rojo
There are no comments available. Be the first to write a comment.