Breast Cancer Stem Cell Potency of Nickel(II)-Polypyridyl Complexes Containing Non-steroidal Anti-inflammatory Drugs.
Breast Cancer Stem Cell Potency of Nickel(II)-Polypyridyl Complexes Containing Non-steroidal Anti-inflammatory Drugs.
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DOI：
10.1002/chem.202001578
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发表时间：
2020-11-02
期刊：
影响因子：
--
通讯作者：
Suntharalingam K
中科院分区：
文献类型：
--
作者：
Feld CJ;Johnson A;Xiao Z;Suntharalingam K
我们报道了两种镍（II）‐3,4,7,8‐四甲基‐1,10‐菲罗啉配合物1和3的乳腺癌干细胞（CSC）效力，它们分别含有非甾体抗炎药（NSAIDs），萘普生和吲哚美辛。镍（II）配合物1和3在微摩尔范围内杀死乳腺csc和大块乳腺癌细胞。值得注意的是，1和3对乳腺CSC的效力与盐霉素（一种已建立的CSC活性药物）相当或更好。复合物1和3对非癌性乳腺上皮细胞的毒性也明显低于乳腺csc或大块乳腺癌细胞（高达4.6倍）。机制研究表明，1和3下调乳腺CSCs中的环氧化酶2 (COX‐2)，并以COX‐2依赖的方式杀死乳腺CSCs。此外，在与坏死性坏死抑制剂（necrostatin - 1和dabrafenib）共同治疗时，1和3对乳腺CSCs的作用减弱，这意味着1和3诱导乳腺CSCs的坏死性坏死（一种有序的坏死形式）。由于细胞凋亡抵抗是CSCs的标志，像1和3这样的化合物可能提供替代（非凋亡）细胞死亡途径，可能是克服难以杀死的CSCs的关键。据我们所知，1和3是第一个与CSCs中COX‐2抑制和坏死性坏死诱导相关的化合物。死亡开关：含有非甾体抗炎药物的NiII -多吡啶复合物通过环氧化酶- 2 （COX - 2）依赖性途径有效地杀死乳腺癌干细胞（CSCs），这种方式被坏死性坏死抑制剂所限制。由于COX - 2过表达和凋亡功能障碍是乳腺CSCs固有的，因此本文提出的化合物可能有助于对抗难以杀死的乳腺CSCs。
We report the breast cancer stem cell (CSC) potency of two nickel(II)‐3,4,7,8‐tetramethyl‐1,10‐phenanthroline complexes, 1 and 3, containing the non‐steroidal anti‐inflammatory drugs (NSAIDs), naproxen and indomethacin, respectively. The nickel(II) complexes, 1 and 3 kill breast CSCs and bulk breast cancer cells in the micromolar range. Notably, 1 and 3 display comparable or better potency towards breast CSCs than salinomycin, an established CSC‐active agent. The complexes, 1 and 3 also display significantly lower toxicity towards non‐cancerous epithelial breast cells than breast CSCs or bulk breast cancer cells (up to 4.6‐fold). Mechanistic studies suggest that 1 and 3 downregulate cyclooxygenase‐2 (COX‐2) in breast CSCs and kill breast CSCs in a COX‐2 dependent manner. Furthermore, the potency of 1 and 3 towards breast CSCs decreased upon co‐treatment with necroptosis inhibitors (necrostatin‐1 and dabrafenib), implying that 1 and 3 induce necroptosis, an ordered form of necrosis, in breast CSCs. As apoptosis resistance is a hallmark of CSCs, compounds like 1 and 3, which potentially provide access to alternative (non‐apoptotic) cell death pathways could hold the key to overcoming hard‐to‐kill CSCs. To the best of our knowledge, 1 and 3 are the first compounds to be associated to COX‐2 inhibition and necroptosis induction in CSCs. Kill switch: NiII‐polypyridyl complexes bearing non‐steroidal anti‐inflammatory drugs are shown to potently kill breast cancer stem cells (CSCs) via a cyclooxygenase‐2 (COX‐2)‐dependent pathway and in a manner that is curtailed by necroptosis inhibitors. As COX‐2 overexpression and apoptosis dysfunction are inherent to breast CSCs, the compounds presented here could help in the fight against hard‐to‐kill breast CSCs.
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