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

doi:10.1002/chem.201701837

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

Chemistry

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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 language	English
Pages (from-to)	9674–9682
Number of pages	9
Journal	CHEMISTRY
Volume	23
Issue number	40
Early online date	27 Jun 2017
DOIs	https://doi.org/10.1002/chem.201701837
Publication status	Published - 18 Jul 2017

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

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.",

author = "Marie Flamme and Cressey, {Paul B.} and Chunxin Lu and Bruno, {Peter M.} and Arvin Eskandari and Hemann, {Michael T.} and Graeme Hogarth and Kogularamanan Suntharalingam",

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T1 - Induction of Necroptosis in Cancer Stem Cells by a Nickel(II)-Dithiocarbamate Phenanthroline Complex

AU - Flamme, Marie

AU - Cressey, Paul B.

AU - Lu, Chunxin

AU - Bruno, Peter M.

AU - Eskandari, Arvin

AU - Hemann, Michael T.

AU - Hogarth, Graeme

AU - Suntharalingam, Kogularamanan

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Y1 - 2017/7/18

N2 - 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.

AB - 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.

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JF - CHEMISTRY

IS - 40

ER -

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

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