Jadomycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism.
Jadomycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism.
复制标题
DOI：
10.1002/prp2.110
复制
发表时间：
2015-03
影响因子：
2.6
通讯作者：
Goralski, Kerry B
中科院分区：
文献类型：
--
作者：
Hall, Steven R;Blundon, Heather L;Ladda, Matthew A;Robertson, Andrew W;Martinez-Farina, Camilo F;Jakeman, David L;Goralski, Kerry B
Jadomycins是由委内瑞拉链霉菌细菌生物合成的天然产物，可杀死培养中的药物敏感和多药耐药乳腺癌细胞。目前，对雅多霉素细胞毒性的机制知之甚少;然而，基于细菌质粒DNA切割研究，建议活性氧（ROS）诱导的DNA切割。本研究的目的是确定ROS是否以及如何在药物敏感的MCF 7（MCF 7-CON）和紫杉醇耐药的MCF 7（MCF 7-TXL）乳腺癌细胞中促进雅多霉素的细胞毒性。如使用细胞内荧光ROS检测探针所测定，雅多霉素B、S、SPhG和F剂量依赖性地增加细胞内ROS活性2.5至5.9倍。与抗氧化剂N-乙酰半胱氨酸共处理降低ROS浓度低于基线水平，并降低相应的细胞毒性效力的四个jadomycins 1.9至3.3倍，证实了ROS介导的机制。添加硫酸铜增强，而添加铜（II）-螯合剂D-青霉胺减少，ROS的产生和细胞毒性的每个jadomycin。抗氧化酶，超氧化物歧化酶1，谷胱甘肽S-转移酶，硫氧还蛋白还原酶，但不是过氧化氢酶，增强雅多霉素介导的ROS的产生和抗癌活性的特异性抑制剂。总之，结果表明，jadomycin细胞毒性涉及通过Cu（II）-jadomycin反应产生胞质超氧化物，这是在MCF 7-CON和耐药MCF 7-TXL细胞中测试和观察到的所有jadomycin的共同机制。超氧化物歧化酶1、谷胱甘肽和过氧化物氧还蛋白/硫氧还蛋白细胞抗氧化酶途径清除由雅多霉素处理产生的细胞内ROS。阻断这些抗氧化剂途径可以作为一种策略，以提高药物敏感和多药耐药乳腺癌中的雅多霉素细胞毒性效力。
Jadomycins are natural products biosynthesized by the bacteria Streptomyces venezuelae which kill drug-sensitive and multidrug-resistant breast cancer cells in culture. Currently, the mechanisms of jadomycin cytotoxicity are poorly understood; however, reactive oxygen species (ROS)–induced DNA cleavage is suggested based on bacterial plasmid DNA cleavage studies. The objective of this study was to determine if and how ROS contribute to jadomycin cytotoxicity in drug-sensitive MCF7 (MCF7-CON) and taxol-resistant MCF7 (MCF7-TXL) breast cancer cells. As determined using an intracellular, fluorescent, ROS-detecting probe, jadomycins B, S, SPhG, and F dose dependently increased intracellular ROS activity 2.5- to 5.9-fold. Cotreatment with the antioxidant N-acetyl cysteine lowered ROS concentrations to below baseline levels and decreased the corresponding cytotoxic potency of the four jadomycins 1.9- to 3.3-fold, confirming a ROS-mediated mechanism. Addition of CuSO4 enhanced, whereas addition of the Cu(II)-chelator d-penicillamine reduced, the ROS generation and cytotoxicity of each jadomycin. Specific inhibitors of the antioxidant enzymes, superoxide dismutase 1, glutathione S-transferase, and thioredoxin reductase, but not catalase, enhanced jadomycin-mediated ROS generation and anticancer activity. In conclusion, the results indicate that jadomycin cytotoxicity involves the generation of cytosolic superoxide via a Cu(II)-jadomycin reaction, a mechanism common to all jadomycins tested and observed in MCF7-CON and drug-resistant MCF7-TXL cells. The superoxide dismutase 1, glutathione, and peroxiredoxin/thioredoxin cellular antioxidant enzyme pathways scavenged intracellular ROS generated by jadomycin treatment. Blocking these antioxidant pathways could serve as a strategy to enhance jadomycin cytotoxic potency in drug-sensitive and multidrug-resistant breast cancers.