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Evaluation of the accumulation of disulfiram and its copper complex in A549 cells using mass spectrometry.
Talanta ( IF 5.6 ) Pub Date : 2020-01-09 , DOI: 10.1016/j.talanta.2020.120732 Xinling Lu 1 , Binxin Lin 2 , Ning Xu 2 , Hua Huang 1 , Yong Wang 3 , Jin-Ming Lin 2
Talanta ( IF 5.6 ) Pub Date : 2020-01-09 , DOI: 10.1016/j.talanta.2020.120732 Xinling Lu 1 , Binxin Lin 2 , Ning Xu 2 , Hua Huang 1 , Yong Wang 3 , Jin-Ming Lin 2
Affiliation
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The famous alcohol-aversion drug disulfiram (DSF) is a promising candidate for repurposing in cancer therapy, as indicated by many ongoing and completed clinical trials. Existing researches focus on demonstrating that the anti-cancer activity of DSF is enhanced by copper ions, or solving the problem that DSF is easily decomposed in the body to lose its activity. However, the metabolic kinetics of its ultimate anti-cancer metabolite DDC-Cu (bis-diethyldithiocarbamate-copper) in cells and how it exerts anti-cancer mechanisms remain unclear. In this work, mass spectrometric evaluation of the intracellular and extracellular accumulation of DSF and its copper complex DDC-Cu was performed. Combined with cytotoxicity assay, staining analysis and flow cytometry, we found that DDC-Cu could easily pass through the cell membrane of A549 cells, and accumulate intracellularly for a long time. This process can lead to cellular morphological changes, an increase in ROS content, cell cycle arrest in the G0/G1 phase and apoptosis. Besides, molecular cancer-relevant targets of DDC-Cu in cancer cells were further discussed. This work investigated the cytotoxic mechanism of DDC-Cu, which has important clinical significance for its application in cancer therapy.
中文翻译：
使用质谱法评估双硫仑及其铜络合物在A549细胞中的积累。
正如许多正在进行和已完成的临床试验所表明的那样，著名的酒精转化药物双硫仑（DSF）是用于癌症治疗的有前途的候选药物。现有研究集中于证明铜离子增强了DSF的抗癌活性，或解决了DSF在体内容易分解而失去其活性的问题。然而，尚不清楚其最终的抗癌代谢产物DDC-Cu（双-二乙基二硫代氨基甲酸酯-铜）在细胞中的代谢动力学及其如何发挥抗癌机制。在这项工作中，对DSF及其铜络合物DDC-Cu的细胞内和细胞外积累进行了质谱评估。结合细胞毒性测定，染色分析和流式细胞仪，我们发现DDC-Cu可以很容易地穿过A549细胞的细胞膜，并长时间在细胞内积累。此过程可导致细胞形态变化，ROS含量增加，细胞周期停滞在G0 / G1期和细胞凋亡。此外，进一步讨论了癌细胞中DDC-Cu的分子癌相关靶标。这项工作研究了DDC-Cu的细胞毒性机制，这对于其在癌症治疗中的应用具有重要的临床意义。
更新日期：2020-01-09
中文翻译：
使用质谱法评估双硫仑及其铜络合物在A549细胞中的积累。
正如许多正在进行和已完成的临床试验所表明的那样，著名的酒精转化药物双硫仑（DSF）是用于癌症治疗的有前途的候选药物。现有研究集中于证明铜离子增强了DSF的抗癌活性，或解决了DSF在体内容易分解而失去其活性的问题。然而，尚不清楚其最终的抗癌代谢产物DDC-Cu（双-二乙基二硫代氨基甲酸酯-铜）在细胞中的代谢动力学及其如何发挥抗癌机制。在这项工作中，对DSF及其铜络合物DDC-Cu的细胞内和细胞外积累进行了质谱评估。结合细胞毒性测定，染色分析和流式细胞仪，我们发现DDC-Cu可以很容易地穿过A549细胞的细胞膜，并长时间在细胞内积累。此过程可导致细胞形态变化，ROS含量增加，细胞周期停滞在G0 / G1期和细胞凋亡。此外，进一步讨论了癌细胞中DDC-Cu的分子癌相关靶标。这项工作研究了DDC-Cu的细胞毒性机制，这对于其在癌症治疗中的应用具有重要的临床意义。
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