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 th eir molecular mechanism of action and relative antineoplastic activity. The first complex, [RuCl2(C6H6)(dmso)], could completely inhibit DNA relaxatio n activity of topoisomerase II and form a drug-induced cleavage complex. Th is strongly suggests that the drug interferes with topoisomerase II activit y by cleavage complex formation. The hi-directional binding of [RuCl4(C6H6) (dmso)] to DNA and topoisomerase II was verified by immunoprecipitation exp eriments which confirmed the presence of DNA and ruthenium in the cleavage complex. The second complex, Ruthenium Salicylaldoxime, could not inhibit t opoisomerase II relaxation activity appreciably and also could not induce c leavage complex formation, though its DNA-binding characteristics and antip roliferation 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 t he first complex and not by the second. A probable mechanism is proposed fo r [RuCl2(C6H6)(dmso)], where the ruthenium atom interacts with DNA and liga nds of the metal atom form cross-links with topoisomerase II. This may faci litate the formation of a drug-induced cleavage complex.