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

Abstract

BACKGROUND:

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-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.

CONCLUSION:

DCQ is the first hypoxia-activated drug showing anti-metastatic effects against breast cancer, suggesting its potential use for breast cancer therapy.

• Authors: Khaled Ghattass, Sally El-Sitt, Kazem Zibara, Saide Rayes, Makhluf J Haddadin, Marwan El-Sabban, Hala Gali-Muhtasib
• Journal: Molecular cancer (Mol Cancer) Vol. 13 Pg. 12 (Jan 24 2014) ISSN: 1476-4598 [Electronic] England
• PMID: 24461075 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Quinoxalines
• RNA, Small Interfering
• quindoxin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (metabolism, pathology)
• Cell Hypoxia (physiology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (drug effects, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Invasiveness (pathology)
• Quinoxalines (pharmacology)
• RNA, Small Interfering
• Signal Transduction (drug effects)
• Transfection
• Xenograft Model Antitumor Assays