Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Etoposide is an effective anticancer agent whose antitumor activity is associated with its phenolic E-ring, which can participate in intracellular redox cycling reactions. Myeloperoxidase (MPO)-catalyzed one-electron oxidation of the etoposide phenolic ring and/or interaction of this phenolic moiety with reactive radicals yields its phenoxyl radical, whose reactivity may determine the pro- or antioxidant effects of this molecule in cells. Using MPO-rich HL-60 cells, we directly demonstrated that both anti- and pro-oxidant activities of etoposide are realized in cells. Etoposide acted as an effective radical scavenger and antioxidant protector of phosphatidylethanolamine, phosphatidylcholine, and other intracellular phospholipids against H2O2-induced oxidation in HL-60 cells with constitutively high MPO activity and in HL-60 cells depleted of MPO by an inhibitor of heme synthesis, succinyl acetone. MPO-catalyzed production of etoposide phenoxyl radicals observed directly in HL-60 cells by electron paramagnetic resonance (EPR) did not result in oxidation of these membrane phospholipids, suggesting that the radicals were not reactive enough to trigger lipid oxidation. MPO-dependent pro-oxidant activity of etoposide was directly demonstrated by (a) the ability of intracellular reduced glutathione (GSH) to eliminate EPR-detectable etoposide phenoxyl radicals, (b) the ability of etoposide phenoxyl radicals to oxidize GSH and protein thiols (after preliminary depletion of intracellular GSH with a maleimide reagent, ThioGlo-1), and (c) the disappearance of these effects after depletion of MPO by pretreatment of cells with succinyl acetone. In addition, titration of intracellular GSH (in intact cells) using the maleimide reagent ThioGlo-1 resulted in remarkably augmented EPR-detectable etoposide phenoxyl radicals and enhanced etoposide-induced topoisomerase II-DNA covalent complexes. In conclusion, the phenolic moiety of etoposide acts as an effective free radical scavenger, accounting for its antioxidant action. Whereas one-electron oxidation of etoposide by free radical scavenging and/or by MPO results in a phenoxyl radical with low reactivity toward lipids, its high reactivity toward thiols is a determinant of its pro-oxidant effects in HL-60 cells.
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PMID:Pro-oxidant and antioxidant mechanisms of etoposide in HL-60 cells: role of myeloperoxidase. 1169 92

Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Since we found that ellipticine also forms the cytochrome P450 (CYP)-mediated covalent DNA adducts, this anticancer drug is considered to function as a pro-drug, whose pharmacological efficiency and/or genotoxic side effects are dependent on its enzymatic activation in target tissues. Here, we demonstrate that ellipticine is also oxidized by peroxidases, which are abundantly expressed in several target tumor tissues. Lactoperoxidase, myeloperoxidase and horseradish peroxidase were used as models. Peroxidases in the presence of hydrogen peroxide oxidize ellipticine to an ellipticine dimer and N(2)-oxide of ellipticine as the major and minor metabolite, respectively. Inhibition of the peroxidase-mediated ellipticine oxidation by radical scavengers ascorbate, glutathione and NADH suggests a one-electron mechanism of the oxidation. The implication of the oxidation of ellipticine by peroxidases in its mechanism of action is discussed.
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PMID:Oxidation of an antitumor drug ellipticine by peroxidases. 1660 8

Myeloperoxidase is expressed exclusively in granulocytes and immature myeloid cells and transforms the topoisomerase II (TOP2) poisons etoposide and mitoxantrone to chemical forms that have altered DNA damaging properties. TOP2 poisons are valuable and widely used anticancer drugs, but they are associated with the occurrence of secondary acute myeloid leukemias. These factors have led to the hypothesis that myeloperoxidase inhibition could protect hematopoietic cells from TOP2 poison-mediated genotoxic damage and, therefore, reduce the rate of therapy-related leukemia. We show here that myeloperoxidase activity leads to elevated accumulation of etoposide- and mitoxantrone-induced TOP2A and TOP2B-DNA covalent complexes in cells, which are converted to DNA double-strand breaks. For both drugs, the effect of myeloperoxidase activity was greater for TOP2B than for TOP2A. This is a significant finding because TOP2B has been linked to genetic damage associated with leukemic transformation, including etoposide-induced chromosomal breaks at the MLL and RUNX1 loci. Glutathione depletion, mimicking in vivo conditions experienced during chemotherapy treatment, elicited further MPO-dependent increase in TOP2A and especially TOP2B-DNA complexes and DNA double-strand break formation. Together these results support targeting myeloperoxidase activity to reduce genetic damage leading to therapy-related leukemia, a possibility that is enhanced by the recent development of novel specific myeloperoxidase inhibitors for use in inflammatory diseases involving neutrophil infiltration.
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PMID:Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy. 2797 36