Triclosan inhibits enoyl-reductase of type I fatty acid synthase in vitro and is cytotoxic to MCF-7 and SKBr-3 breast cancer cells
Triclosan inhibits enoyl-reductase of type I fatty acid synthase in vitro and is cytotoxic to MCF-7 and SKBr-3 breast cancer cells
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DOI：
10.1007/s00280-001-0399-x
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发表时间：
2002-03-01
影响因子：
3
通讯作者：
Anderson, VE
中科院分区：
文献类型：
--
作者：
Liu, BQ;Wang, YQ;Anderson, VE
背景和目的：人I型脂肪酸合成酶被认为是乳腺癌的化疗靶点，其基础是蓝菌素使人β-酮酰基合成酶活性失活。三氯生是一种常见的抗生素，它通过抑制敏感细菌中11型脂肪酸合成酶的Enoyl-Reductase发挥作用。如果三氯生是人类脂肪酸合成酶的抑制剂，如果抑制脂肪酸合成酶对乳腺癌细胞系有毒性，那么三氯生可能被证明是治疗乳腺癌的先导化合物。因此，我们在细胞培养中研究了三氯生对脊椎动物I型脂肪酸合成酶的抑制活性及其对乳腺癌细胞株的影响。方法：采用分光光度法研究三氯生对人和鹅脂肪酸合成酶的抑制活性及各部分反应。观察不同浓度的三氯生对体外培养的MCF-7和SKBR-3细胞生长的抑制作用和对细胞存活率的影响。结果：动力学研究表明，三氯生是人和鹅I型脂肪酸合成酶的慢结合抑制剂，对环烯醇基还原酶部分活性有抑制作用，IC50值在10~50微米之间。相似浓度的三氯生对体外培养的MCF-7和SKBR-3细胞的活力和生长均有抑制作用。结论：本研究结果证实了脂肪酸合酶可能是乳腺癌化疗靶点的假说，提示脂肪酸合酶烯醇还原酶部分活性的抑制剂可能具有化疗潜力。
Background and purpose: Human type I fatty acid synthase has been proposed as a chemotherapeutic target for the treatment of breast cancer based on the inactivation of human beta-ketoacyl synthase activity by cerulenin. Triclosan, a common antibiotic, functions by inhibiting the enoyl-reductase enzymes of type 11 fatty acid synthases in susceptible bacteria. If triclosan is an inhibitor of human fatty acid synthase and if inhibition of fatty acid synthase is toxic to breast cancer cell lines , triclosan could prove to be a lead compound for the treatment of breast cancer. Consequently, the inhibitory activity of triclosan against vertebrate type I fatty acid synthases and its effects on breast cancer lines in cell culture were investigated. Methods: The inhibitory activities of triclosan against human and goose fatty acid synthases and each of the partial reactions were investigated using spectrophotometric assays. The ability of triclosan at various concentrations to inhibit growth and reduce the viability of MCF-7 and SKBr-3 cells in culture was evaluated. Results: Kinetic studies showed triclosan to be a slow binding inhibitor of human and goose type I fatty acid synthase and to inhibit the partial activity of enoyl-reductase with IC50 values between 10 and 50 muM. Triclosan at similar concentrations was also shown to inhibit both viability and growth of MCF-7 and SKBr-3 cells in culture. Conclusions: The results corroborate the hypothesis that fatty acid synthase may be a target of breast cancer chemotherapy and suggest that inhibitors of the enoyl-reductase partial activity of fatty acid synthase may have chemotherapeutic potential.