Single cell mass spectrometry analysis of drug-resistant cancer cells: Metabolomics studies of synergetic effect of combinational treatment.
Single cell mass spectrometry analysis of drug-resistant cancer cells: Metabolomics studies of synergetic effect of combinational treatment.
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DOI：
10.1016/j.aca.2022.339621
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发表时间：
2022-04-08
影响因子：
6.2
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Chen X;Sun M;Yang Z
伊立替康 (IRI) 是一种阻断 DNA 合成的拓扑异构酶 I 抑制剂，是一种广泛用于治疗转移性结直肠癌的化疗药物。尽管是一种有效的化疗药物，但其临床有效性受到内在和获得性耐药性的限制。先前的研究表明，IRI 会诱导伊立替康耐药（IRI 耐药）细胞的癌症干细胞性。二甲双胍是一种口服抗糖尿病药物，最近据报道具有抗癌作用，这可能是由于它选择性杀死癌症干细胞 (CSC)。鉴于 IRI 抗性细胞表现出高度的癌症干性，我们假设二甲双胍可以使 IRI 抗性细胞变得敏感并挽救治疗效果。在这项工作中，我们利用单探针质谱技术来分析不同处理条件下的活 IRI 抗性细胞。我们发现二甲双胍治疗可能通过抑制脂肪酸合酶 (FASN) 与脂质和脂肪酸的下调相关。重要的是，某些物种只能从处于存活状态的细胞中检测到。使用 Chou-Talalay 组合指数评价二甲双胍和 IRI 共同治疗 IRI 耐药细胞的协同效应水平。使用酶活性测定，我们确定与 IRI 或二甲双胍单一治疗相比，联合治疗表现出最高的 FASN 抑制作用。据我们所知，这是第一个单细胞 MS 代谢组学研究，证明二甲双胍-IRI 协同作用可克服 IRI 耐药细胞的耐药性。
Irinotecan (IRI), a topoisomerase I inhibitor blocking DNA synthesis, is a widely used chemotherapy drug for metastatic colorectal cancer. Despite being an effective chemotherapy drug, its clinical effectiveness is limited by both intrinsic and acquired drug resistance. Previous studies indicate IRI induces cancer stemness in irinotecan-resistant (IRI-resistant) cells. Metformin, an oral antidiabetic drug, was recently reported for anticancer effects, likely due to its selective killing of cancer stem cells (CSCs). Given IRI-resistant cells exhibiting high cancer stemness, we hypothesize metformin can sensitize IRI-resistant cells and rescue the therapeutic effect. In this work, we utilized the Single-probe mass spectrometry technique to analyze live IRI-resistant cells under different treatment conditions. We discovered that metformin treatment was associated with the downregulation of lipids and fatty acids, potentially through the inhibition of fatty acid synthase (FASN). Importantly, certain species can be only detected from cells in their living status. The level of synergistic effect of metformin and IRI in their co-treatment of IRI-resistant cells was evaluated using Chou-Talalay combinational index. Using enzymatic activity assay, we determined that the co-treatment exhibit the highest FASN inhibition compared with the mono-treatment of IRI or metformin. To our knowledge, this is the first single-cell MS metabolomics study demonstrating metformin-IRI synergistic effect overcoming drug resistance in IRI-resistant cells.
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