A unique paclitaxel-mediated modulation of the catalytic activity of topoisomerase IIalpha.
Paclitaxel (Taxol) is known to act by polymerizing and stabilizing microtubules. In spite of a known target, the existence of additional targets is suggested by a poor understanding of the mechanism(s) underlying eventual cell death by paclitaxel and by the drug's high efficacy, as compared to other spindle poisons. Based on the enhanced sensitivity of a mutant DNA double-strand break repair-deficient Chinese hamster ovary cell line to paclitaxel as well as to various topoisomerase (Topo) II poisons, it was hypothesized that paclitaxel, in addition to having an effect on microtubules, may also alter the activity of Topo II. This study demonstrates the unique, in vitro effects of paclitaxel on Topo II activity as investigated by monitoring the decatenation of kinetoplast DNA and relaxation of supercoiled plasmid DNA by Topo II. Unlike classical anti-topoisomerase drugs, low concentrations of paclitaxel (0.02-500 nM) stimulated Topo II catalytic activity, while higher concentrations over 5 microM inhibited the activity of Topo II. Furthermore, these effects of paclitaxel appear to be mediated through a direct interaction of paclitaxel with Topo II rather than an interaction with DNA or DNA-Topo II complexes. Collectively, the evidence presented suggests the existence of an atypical interaction between Topo II and paclitaxel that may disrupt the normal functioning of the enzyme.
Dhawan
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Division of Basic Pharmaceutical Sciences, School of Pharmacy, Northeast Louisiana University, Monroe 71209, USA.
Swaffar
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DS
D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D016466:CHO Cells; D002384:Catalysis; D002417:Cattle; D006224:Cricetinae; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D017239:Paclitaxel / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D004247:DNA; D004250:DNA Topoisomerases, Type II; D017239:Paclitaxel