Induction of Necroptosis in Cancer Stem Cells by a Nickel(II)-Dithiocarbamate Phenanthroline Complex

Marie Flamme, Paul B. Cressey, Chunxin Lu, Peter M. Bruno, Arvin Eskandari, Michael T. Hemann, Graeme Hogarth, Kogularamanan Suntharalingam

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Abstract

The cytotoxic properties of a series of nickel(II)-dithiocarbamatephenanthroline complexes is reported. The complexes, 1-6 kill bulk cancer cellsand cancer stem cells (CSCs) with micromolar potency. Two of the complexes, 2and 6 kill breast cancer stem cell (CSC)-enriched HMLER-shEcad cells 2-foldbetter than breast CSC-depleted HMLER cells. Complex 2 inhibits mammosphereformation to a similar extent as salinomycin (a CSCspecific toxin). Detailedmechanistic studies suggest that 2 induces CSC death by necroptosis, aprogrammed form of necrosis. Specifically, 2 triggers MLKL phosphorylation,oligomerization and translocation to the cell membrane. Further, 2 inducesnecrosomemediated propidium iodide (PI) uptake and mitochondrial membrane depolarisation,and morphological changes consistent with necroptotosis. Strikingly, 2 does notevoke necroptosis by intracellular reactive oxygen species (ROS) production orpoly ADP ribose polymerase (PARP-1) activation.

Original languageEnglish
Pages (from-to)9674–9682
Number of pages9
JournalCHEMISTRY
Volume23
Issue number40
Early online date27 Jun 2017
DOIs
Publication statusPublished - 18 Jul 2017

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