A Breast Cancer Stem Active Cobalt(III)-Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential.
A Breast Cancer Stem Active Cobalt(III)-Cyclam Complex Containing Flufenamic Acid with Immunogenic Potential.
复制标题
一种乳腺癌干活性钴 (III)-仙客来复合物，含有具有免疫原性潜力的氟芬那酸。
DOI：
10.1002/anie.202317940
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Suntharalingam,Kogularamanan
中科院分区：
文献类型：
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作者：
Fang,Jiaxin;Orobator,OwamagbeN;Olelewe,Chibuzor;Passeri,Ginevra;Singh,Kuldip;Awuah,SamuelG;Suntharalingam,Kogularamanan
在抗癌干细胞（CSC）药物发现的背景下，报告了携带非甾体抗炎药氟芬那酸的钴（III）-cyclam复合物的细胞毒性和免疫原性激活特性。钴（III）-cyclam络合物1对单层生长的乳腺CSC显示出亚微摩尔效力，分别是盐霉素（一种已确立的抗乳腺CSC药物）和顺铂（一种抗癌金属药物）的24倍和31倍。引人注目的是，钴（III）-cyclam络合物1对三维培养的乳腺CSC乳腺球的效力是盐霉素和顺铂的69倍和50倍。机制研究表明，1诱导DNA损伤，抑制环氧合酶-2表达，并促进caspase依赖性凋亡。用1处理的乳腺CSC表现出免疫原性细胞死亡的损伤相关分子模式，并被巨噬细胞吞噬。据我们所知，1是第一个任何氧化态或几何形状的钴络合物，对乳腺CSC表现出细胞毒性和免疫原性激活作用。
The cytotoxic and immunogenic‐activating properties of a cobalt(III)‐cyclam complex bearing the non‐steroidal anti‐inflammatory drug, flufenamic acid is reported within the context of anti‐cancer stem cell (CSC) drug discovery. The cobalt(III)‐cyclam complex1displays sub‐micromolar potency towards breast CSCs grown in monolayers, 24‐fold and 31‐fold greater than salinomycin (an established anti‐breast CSC agent) and cisplatin (an anticancer metallopharmaceutical), respectively. Strikingly, the cobalt(III)‐cyclam complex1is 69‐fold and 50‐fold more potent than salinomycin and cisplatin towards three‐dimensionally cultured breast CSC mammospheres. Mechanistic studies reveal that1induces DNA damage, inhibits cyclooxygenase‐2 expression, and prompts caspase‐dependent apoptosis. Breast CSCs treated with1exhibit damage‐associated molecular patterns characteristic of immunogenic cell death and are phagocytosed by macrophages. As far as we are aware,1is the first cobalt complex of any oxidation state or geometry to display both cytotoxic and immunogenic‐activating effects on breast CSCs.