ArticleMolecular cancer2014
The quinoxaline di-N-oxide DCQ blocks breast cancer metastasis in vitro and in vivo by targeting the hypoxia inducible factor-1 pathway.
Article in Molecular cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 48 citations in OpenAlex.
- Cell-cell communication characteristics in breast cancer metastasis.Cell communication and signaling : CCS · 2024Review
- Exploring the pharmacological mechanism of compound kushen injection in the treatment of breast cancer usingFrontiers in oncology · 2022Article
- Synthesis of 7-amino-6-halogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: a way forward for targeting hypoxia and drug resistance of cancer cells.RSC advances · 2021Article
- One-pot sequential coupling reactions as a new practical protocol for the synthesis of unsymmetrical 2,3-diethynyl quinoxalines and 4-ethynyl-substituted pyrrolo[1,2-a]quinoxalines.Molecular diversity · 2021Article
- Long non-coding RNA ZFAS1 promotes the expression of EPAS1 in gastric cardia adenocarcinoma.Journal of advanced research · 2021Article
- Elevated GALNT10 expression identifies immunosuppressive microenvironment and dismal prognosis of patients with high grade serous ovarian cancer.Cancer immunology, immunotherapy : CII · 2020Article
- Synthesis and Properties of Quinoxaline-Containing Benzoxazines and Polybenzoxazines.ACS omega · 2019Article
- Effects of VEGFR1Journal of cancer research and clinical oncology · 2019Article
- Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database.Therapeutic advances in medical oncology · 2019Article
- Vandetanib (ZD6474) induces antiangiogenesis through mTOR-HIF-1 alpha-VEGF signaling axis in breast cancer cells.OncoTargets and therapy · 2018Article
- Organotropism: new insights into molecular mechanisms of breast cancer metastasis.NPJ precision oncology · 2018Review
- Mechanisms underlying the antiproliferative effects of a series of quinoxaline-derived chalcones.Scientific reports · 2017Article
- Synthesis and Evaluation of New Quinoxaline Derivatives of Dehydroabietic Acid as Potential Antitumor Agents.Molecules (Basel, Switzerland) · 2017Article
- The photoprotective effects of 2-benzoyl-3-phenylquinoxaline 1,4-dioxide against UVB-induced damage in HaCaT cells.Medical oncology (Northwood, London, England) · 2016Article
- Genotoxic risk of quinocetone and its possible mechanism inToxicology research · 2016Article
- Quinoxaline 1,4-di-N-Oxides: Biological Activities and Mechanisms of Actions.Frontiers in pharmacology · 2016Review
- Assessment of caroverine as a potential chemotherapeutical agent in HNSCC cell lines.European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2015Article
- Hypoxia-induced carbonic anhydrase IX facilitates lactate flux in human breast cancer cells by non-catalytic function.Scientific reports · 2015Article
- Mechanisms involved in breast cancer liver metastasis.Journal of translational medicine · 2015Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
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Abstract
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.
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