Topoisomerase II inhibitors induce cleavage of nuclear and 35-kb plastid DNAs in the malarial parasite Plasmodium falciparum.
The topoisomerase II-specific inhibitors VP-16 and ciprofloxacin were used to investigate the presence of topoisomerase II activities associated with nuclear and 35-kb plastid DNAs of the malarial parasite Plasmodium falciparum. The eukaryotic topoisomerase II inhibitor VP-16 induced cleavage of both nuclear and 35-kb parasite DNAs. In contrast, ciprofloxacin, a fluoroquinolone drug known to act on the bacterial type II topoisomerase DNA gyrase, only induced cleavage of the Plasmodial 35-kb DNA. Drug-induced cleavage resulted in the protection of the 5'- but not 3'- ends of the cleaved nuclear and 35-kb DNAs from exonuclease digestion, suggesting that the 5'-ends of the broken DNA were protein-linked, a property reminiscent of DNA cleavage mediated by topoisomerase II enzymes. Furthermore, DNA cleavage induced by both VP-16 and ciprofloxacin was heat-reversible. This is the first evidence that P. falciparum contains two distinct topoisomerase II activities that are molecular targets for chemotherapeutic agents.
Weissig
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Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville 32610-0267, USA.
Vetro-Widenhouse
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Rowe
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TC
D000818:Animals; D002939:Ciprofloxacin / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004270:DNA, Circular / Q000187:drug effects / Q000378:metabolism; D016054:DNA, Protozoan / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology*; D005092:Exonucleases / Q000378:metabolism; D006358:Hot Temperature; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D059005:Topoisomerase II Inhibitors
D004270:DNA, Circular; D016054:DNA, Protozoan; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D002939:Ciprofloxacin; D005047:Etoposide; D005092:Exonucleases; D004250:DNA Topoisomerases, Type II