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Cancer Stem Cell and Bulk Cancer Cell Active Copper(II) Complexes with Vanillin Schiff Base Derivatives and Naproxen
Author(s) -
Lu Chunxin,
Eskandari Arvin,
Cressey Paul B.,
Suntharalingam Kogularamanan
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201701939
Subject(s) - chemistry , cancer cell , cancer stem cell , apoptosis , dna damage , salinomycin , programmed cell death , topoisomerase , naproxen , dna , reactive oxygen species , biochemistry , cancer , cancer research , biology , medicine , genetics , alternative medicine , pathology , antibiotics
Four copper(II) complexes, 1 – 4 containing regioisomeric vanillin Schiff base derivatives and the nonsteroidal anti‐inflammatory drug (NSAID), naproxen, were synthesised and characterised. All complexes effectively cleave DNA in cell‐free systems, with 4 displaying the highest nuclease activity. DNA binding studies suggest that 4 binds to DNA via the grooves prior to inducing oxidative DNA cleavage. Three of the complexes ( 1 , 3 , and 4 ) indiscriminately kill cancer stem cell (CSC)‐enriched cells (HMLER‐shEcad) and bulk cancer cells (HMLER) at micromolar concentrations. The most effective complex, 4 also reduced the formation and size of mammospheres to a similar extent as salinomycin, a well‐established CSC‐potent agent. Mechanistic studies show that 4 is readily taken up by CSCs, elevates intracellular reactive oxygen species (ROS) levels, causes DNA damage, and induces caspase‐dependent apoptosis. Furthermore, 4 inhibits cyclooxygenase‐2 (COX‐2) expression and causes COX‐2‐dependent CSC death. The advantage of 4 over bulk cancer cell‐ or CSC‐selective agents is that it has the potential to remove whole tumor populations (bulk cancer cells and CSCs) with a single dose.