使用镍（II）-二硫代氨基甲酸菲咯啉配合物诱导肿瘤干细胞发生细胞坏死。
Induction of Necroptosis in Cancer Stem Cells using a Nickel(II)-Dithiocarbamate Phenanthroline Complex.
机构信息
Department of Chemistry, King's College London, London, SE1 1DB, UK.
The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA.
出版信息
Chemistry. 2017 Jul 18;23(40):9674-9682. doi: 10.1002/chem.201701837. Epub 2017 Jun 27.
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.
本文报道了一系列镍（II）-二硫代氨基甲酸盐菲咯啉配合物的细胞毒性特性。这些配合物 1-6 以微摩尔效力杀死大量癌细胞和癌症干细胞（CSC）。其中两种配合物 2 和 6 杀死富含乳腺癌干细胞（CSC）的 HMLER-shEcad 细胞的数量是乳腺癌 CSC 耗尽的 HMLER 细胞的两倍。复合物 2 抑制类球体形成的程度与博来霉素（一种 CSC 特异性毒素）相似。详细的机制研究表明，2 通过坏死细胞程序性死亡（necroptosis）诱导 CSC 死亡。具体而言，2 触发 MLKL 磷酸化、寡聚化和向细胞膜易位。此外，2 诱导坏死体介导的碘化丙啶（PI）摄取和线粒体膜去极化，以及与坏死细胞程序性死亡一致的形态变化。引人注目的是，2 不会通过细胞内活性氧（ROS）产生或聚（ADP-核糖）聚合酶（PARP-1）激活引起坏死细胞程序性死亡。
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