Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species

BMC Cancer

Maamoun Fatfat³  Raghida Abou Merhi¹  Omar Rahal³  Detcho A Stoyanovsky²  Angela Zaki³  Hazar Haidar³  Valerian E Kagan²  Hala Gali-Muhtasib³  Khaled Machaca⁴ 

[1] Department of Biology, Lebanese University, Beirut, Lebanon

[2] Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, USA

[3] Department of Biology, American University of Beirut, Beirut, Lebanon

[4] Department of Physiology and Biophysics, Weill Cornell Medical College, Doha, Qatar

关键词: Reactive oxygen species;    Copper;    Redox cycling;    TPEN;    Metal chelation;    Colon cancer;   

Others  :  1125316
DOI  :  10.1186/1471-2407-14-527

 received in 2013-10-21, accepted in 2014-07-15,  发布年份 2014

【 摘 要 】

Background

Metals including iron, copper and zinc are essential for physiological processes yet can be toxic at high concentrations. However the role of these metals in the progression of cancer is not well defined. Here we study the anti-tumor activity of the metal chelator, TPEN, and define its mechanism of action.

Methods

Multiple approaches were employed, including cell viability, cell cycle analysis, multiple measurements of apoptosis, and mitochondrial function. In addition we measured cellular metal contents and employed EPR to record redox cycling of TPEN–metal complexes. Mouse xenografts were also performed to test the efficacy of TPEN in vivo.

Results

We show that metal chelation using TPEN (5μM) selectively induces cell death in HCT116 colon cancer cells without affecting the viability of non-cancerous colon or intestinal cells. Cell death was associated with increased levels of reactive oxygen species (ROS) and was inhibited by antioxidants and by prior chelation of copper. Interestingly, HCT116 cells accumulate copper to 7-folds higher levels than normal colon cells, and the TPEN-copper complex engages in redox cycling to generate hydroxyl radicals. Consistently, TPEN exhibits robust anti-tumor activity in vivo in colon cancer mouse xenografts.

Conclusion

Our data show that TPEN induces cell death by chelating copper to produce TPEN-copper complexes that engage in redox cycling to selectively eliminate colon cancer cells.

【 授权许可】

   
2014 Fatfat et al.; licensee BioMed Central Ltd.

【 图 表 】

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