Inhibition of topoisomerase II catalytic activity by two ruthenium compounds: a ligand-dependent mode of action.
The ability of two structurally different ruthenium complexes to interfere with the catalytic activity of topoisomerase II was studied to elucidate their molecular mechanism of action and relative antineoplastic activity. The first complex, [RuCl2(C6H6)(dmso)], could completely inhibit DNA relaxation activity of topoisomerase II and form a drug-induced cleavage complex. This strongly suggests that the drug interferes with topoisomerase II activity by cleavage complex formation. The bi-directional binding of [RuCl2(C6H6)(dmso)] to DNA and topoisomerase II was verified by immunoprecipitation experiments which confirmed the presence of DNA and ruthenium in the cleavage complex. The second complex, Ruthenium Salicylaldoxime, could not inhibit topoisomerase II relaxation activity appreciably and also could not induce cleavage complex formation, though its DNA-binding characteristics and antiproliferation activity were almost comparable to those of [RuCl2(C6H6)(dmso)]. The results suggest that the difference in ligands and their orientation around a metal atom may be responsible for topoisomerase II poisoning by the first complex and not by the second. A probable mechanism is proposed for [RuCl2(C6H6)(dmso)], where the ruthenium atom interacts with DNA and ligands of the metal atom form cross-links with topoisomerase II. This may facilitate the formation of a drug-induced cleavage complex.
Gopal
Y N
YN
Department of Biochemistry, School of Life Sciences, University of Hyderabad, India.
Jayaraju
D
D
Kondapi
A K
AK
D000251:Adenosine Triphosphatases / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002384:Catalysis / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D011088:DNA Ligases / Q000737:chemistry; D004121:Dimethyl Sulfoxide / Q000138:chemical synthesis / Q000494:pharmacology*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D008024:Ligands; D046911:Macromolecular Substances; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017975:Ruthenium Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D008024:Ligands; D046911:Macromolecular Substances; D009942:Organometallic Compounds; C118522:Ruthenium Ben; D017975:Ruthenium Compounds; C118523:Ruthenium Sal; D059005:Topoisomerase II Inhibitors; D004247:DNA; D000251:Adenosine Triphosphatases; D011088:DNA Ligases; D004121:Dimethyl Sulfoxide