Inhibition of Human Tyrosyl-DNA Phosphodiesterase by Aminoglycoside Antibiotics and Ribosome Inhibitors Export

@article{citeulike:5835996, abstract = {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. 10.1124/mol.105.021865}, author = {Liao, Zhiyong and Thibaut, Laurent and Jobson, Andrew and Pommier, Yves}, citeulike-article-id = {5835996}, citeulike-linkout-0 = {http://dx.doi.org/10.1124/mol.105.021865}, citeulike-linkout-1 = {http://molpharm.aspetjournals.org/content/70/1/366.abstract}, citeulike-linkout-2 = {http://molpharm.aspetjournals.org/content/70/1/366.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/16618796}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=16618796}, day = {1}, doi = {10.1124/mol.105.021865}, journal = {Mol Pharmacol}, keywords = {inhibitors, tdp1}, month = {July}, number = {1}, pages = {366--372}, posted-at = {2009-09-24 15:27:24}, priority = {2}, title = {Inhibition of Human Tyrosyl-DNA Phosphodiesterase by Aminoglycoside Antibiotics and Ribosome Inhibitors}, url = {http://dx.doi.org/10.1124/mol.105.021865}, volume = {70}, year = {2006} }

TY - JOUR ID - citeulike:5835996 L3 - citeulike-article-id:5835996 N2 - 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. 10.1124/mol.105.021865 IS - 1 JF - Mol Pharmacol EP - 372 TI - Inhibition of Human Tyrosyl-DNA Phosphodiesterase by Aminoglycoside Antibiotics and Ribosome Inhibitors VL - 70 SP - 366 KW - inhibitors KW - tdp1 AU - Liao, Zhiyong AU - Thibaut, Laurent AU - Jobson, Andrew AU - Pommier, Yves PY - 2006/07/01/ UR - http://dx.doi.org/10.1124/mol.105.021865 ER -