4 years ago

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

Induction of Necroptosis in Cancer Stem Cells using a Nickel(II)-Dithiocarbamate Phenanthroline Complex
Graeme Hogarth, Arvin Eskandari, Peter M. Bruno, Paul B. Cressey, Kogularamanan Suntharalingam, Chunxin Lu, Marie Flamme, Michael T. Hemann
The cytotoxic properties of a series of nickel(II)-dithiocarbamate phenanthroline complexes is reported. The complexes 1–6 kill bulk cancer cells and cancer stem cells (CSCs) with micromolar potency. Two of the complexes, 2 and 6, kill twice as many breast cancer stem cell (CSC)-enriched HMLER-shEcad cells as compared to breast CSC-depleted HMLER cells. Complex 2 inhibits mammosphere formation to a similar extent as salinomycin (a CSC-specific toxin). Detailed mechanistic studies suggest that 2 induces CSC death by necroptosis, a programmed form of necrosis. Specifically, 2 triggers MLKL phosphorylation, oligomerization, and translocation to the cell membrane. Additionally, 2 induces necrosome-mediated propidium iodide (PI) uptake and mitochondrial membrane depolarisation, as well as morphological changes consistent with necroptotosis. Strikingly, 2 does not evoke necroptosis by intracellular reactive oxygen species (ROS) production or poly(ADP) ribose polymerase (PARP-1) activation. Necroptonomicon: Multi-drug resistant pathways, including apoptosis dysfunction, are operative in cancer stem cells (CSCs), and thus apoptosis-inducing chemotherapies are largely ineffective against this class of cancer cells. Therefore, the discoveries of chemical agents that can induce CSC death through non-apoptotic pathways are highly valuable in the fight against cancer. Here we report the first nickel complex to induce CSC death by necroptosis, an ordered form of necrosis.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701837

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