title: Breast Cancer Stem Cell Potent Copper(II)-Non-Steroidal Anti-Inflammatory Drug Complexes.
abstract: 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.
authors.affiliation: Department of Chemistry, King's College London, London, SE1 1DB, UK.
authors.forename: Janine N
authors.initials: JN
authors.lastname: Boodram
authors.affiliation: Department of Chemistry, King's College London, London, SE1 1DB, UK.
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Mcgregor
authors.affiliation: The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Bruno
authors.affiliation: Department of Chemistry, King's College London, London, SE1 1DB, UK.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Cressey
authors.affiliation: The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hemann
authors.affiliation: Department of Chemistry, King's College London, London, SE1 1DB, UK. kogularamanan.suntharalingam@kcl.ac.uk.
authors.forename: Kogularamanan
authors.identifier: http://orcid.org/0000-0002-7047-6384
authors.initials: K
authors.lastname: Suntharalingam
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D003300:Copper / Q000737:chemistry*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017382:Reactive Oxygen Species; D003300:Copper; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
keywords: COX inhibition; bioinorganic chemistry; cancer; nonsteroidal anti-inflammatory drugs; reactive oxygen species