Liao Zhiyong, Thibaut Laurent, Jobson Andrew, Pommier Yves
Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Mol Pharmacol. 2006 Jul;70(1):366-72. doi: 10.1124/mol.105.021865. Epub 2006 Apr 17.
DNA topoisomerase I (Top1) is the target of camptothecin, and novel Top1 inhibitors are in development as anticancer agents. Top1 inhibitors damage DNA by trapping covalent complexes between the Top1 catalytic tyrosine and the 3'-end of the broken DNA. Tyrosyl-DNA phosphodiesterase (Tdp1) can repair Top1-DNA covalent complexes by hydrolyzing the tyrosyl-DNA bond. Inhibiting Tdp1 has the potential to enhance the anticancer activity of Top1 inhibitors (http://discover.nci.nih.gov/pommier/pommier.htm) and to act as antiproliferative agents. In the present study, we report that neomycin inhibits Tdp1 more effectively than the related aminoglycosides paromomycin and lividomycin A. Inhibition of Tdp1 by neomycin is observed both with single- and double-stranded substrates but is slightly stronger with duplex DNA, which is different from aclarubicin, which only inhibits Tdp1 with the double-stranded substrate. Inhibition by neomycin can be overcome with excess Tdp1 and is greatest at low pH. To our knowledge, aminoglycoside antibiotics and the ribosome inhibitors thiostrepton, clindamycin-2-phosphate, and puromycin are the first reported pharmacological Tdp1 inhibitors.
DNA拓扑异构酶I（Top1）是喜树碱的作用靶点，新型Top1抑制剂正作为抗癌药物进行研发。Top1抑制剂通过捕获Top1催化酪氨酸与断裂DNA的3'-末端之间的共价复合物来损伤DNA。酪氨酰-DNA磷酸二酯酶（Tdp1）可通过水解酪氨酰-DNA键来修复Top1-DNA共价复合物。抑制Tdp1有可能增强Top1抑制剂的抗癌活性（http://discover.nci.nih.gov/pommier/pommier.htm）并作为抗增殖剂发挥作用。在本研究中，我们报告新霉素比相关氨基糖苷类药物巴龙霉素和青紫霉素A更有效地抑制Tdp1。新霉素对Tdp1的抑制作用在单链和双链底物上均有观察到，但对双链DNA的抑制作用稍强，这与阿克拉霉素不同，阿克拉霉素仅对双链底物抑制Tdp1。过量的Tdp1可克服新霉素的抑制作用，且在低pH值下抑制作用最强。据我们所知，氨基糖苷类抗生素以及核糖体抑制剂硫链丝菌素、磷酸克林霉素和嘌呤霉素是首次报道的药理学Tdp1抑制剂。
