A Small Molecule Inhibits Protein Disulfide Isomerase and Triggers the Chemosensitization of Cancer Cells
A Small Molecule Inhibits Protein Disulfide Isomerase and Triggers the Chemosensitization of Cancer Cells
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DOI：
10.1002/anie.201406577
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发表时间：
2014-11-17
影响因子：
16.6
通讯作者：
Vollmar, Angelika M.
中科院分区：
文献类型：
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作者：
Eirich, Juergen;Braig, Simone;Vollmar, Angelika M.
对化学治疗剂的抗性代表癌症研究中的主要挑战。解决这一问题的一种方法是联合治疗，即将毒性化疗药物与敏化化合物一起应用，以解决癌细胞诱导凋亡的脆弱性。在这里，我们报告了一个新的化合物类（T8），敏感的各种癌细胞对依托泊苷治疗在亚毒性浓度的发现。蛋白质组学分析显示蛋白质二硫键异构酶（PDI）作为T8类的目标。深入的化学和生物学研究，如优化化合物的合成、分子对接分析、细胞成像和细胞凋亡测定，证实了通过可逆PDI抑制的独特作用模式。
Resistance to chemotherapeutic agents represents a major challenge in cancer research. One approach to this problem is combination therapy, the application of a toxic chemotherapeutic drug together with a sensitizing compound that addresses the vulnerability of cancer cells to induce apoptosis. Here we report the discovery of a new compound class (T8) that sensitizes various cancer cells towards etoposide treatment at subtoxic concentrations. Proteomic analysis revealed protein disulfide isomerase (PDI) as the target of the T8 class. In-depth chemical and biological studies such as the synthesis of optimized compounds, molecular docking analyses, cellular imaging, and apoptosis assays confirmed the unique mode of action through reversible PDI inhibition.