Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 55, Issue 8, Pages 2845-2850Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201510443
Keywords
bioinorganic chemistry; cancer; COX inhibition; nonsteroidal anti-inflammatory drugs; reactive oxygen species
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Funding
- Leverhulme Trust [ECF-2014-178]
- King's College London Research Fellowship
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The breast cancer stem cell (CSC) potency of a series of copper(II)-phenanthroline complexes containing the nonsteroidal anti-inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4, selectivity kills breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC-specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis. Breast cancer recurrence is strongly linked to the existence
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