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.
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。
