title: Changes in the activity of antioxidant barrier after treatment of K562 and CCRF-CEM cell lines with doxorubicin-transferrin conjugate.
abstract: Doxorubicin (DOX), one of the oldest member of the anthracycline antibiotics, has been administered for over 50 years to patients with leukemias and solid tumors. However, the high unspecified DOX toxicity, related to reactive oxygen species (ROS), affects its limitation in clinical application. Therefore we proposed the usage of human transferrin as a doxorubicin carrier in order to improve the quality of doxorubicin application in conventional chemotherapy. In this study we continue our investigations related to the mechanism of the toxicity of doxorubicin-transferrin (DOX-TRF) conjugate in human leukemia cells. Consequently, we are now concentrating on the influence of this compound on the antioxidative system in K562 and CCRF-CEM cell lines (chronic erythromyeloblastoid leukemia and acute lymphoblastic leukemia cells, respectively). We carried out a neutral red cytotoxicity assay, reduced (GSH) and total (GSH + GSSG) glutathione content, alterations in the activity of catalase and enzymes responsible for maintaining glutathione in reduced form. Exposure of leukemia cells to the investigated anticancer agents caused a time-dependent depletion of intracellular GSH, accompanied by an increase of catalase activity. Moreover, analysis of GSH-related enzymes showed a significant increase in the activities of thioredoxin reductase and glutathione peroxidase after DOX-TRF application. In contrast, glutathione reductase activity was reduced by conjugate treatment to 50%. Significant differences between the pro-oxidative actions of the investigated anticancer compounds were observed in RT-PCR experiments, which confirmed that changes in the activity of catalase and GSH-related enzymes are strictly correlated with their gene transcription changes.
authors.affiliation: Department of Thermobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Street, 90-236 Lodz, Poland. Electronic address: szwedma@biol.uni.lodz.pl.
authors.forename: Marzena
authors.initials: M
authors.lastname: Szwed
authors.affiliation: Laboratory of Transcriptional Regulation, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Łódź, Poland.
authors.forename: Katarzyna D
authors.initials: KD
authors.lastname: Kania
authors.affiliation: Department of Thermobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Street, 90-236 Lodz, Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Jozwiak
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004337:Drug Carriers; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D014168:Transferrin / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D004337:Drug Carriers; D004798:Enzymes; D014168:Transferrin; C000599870:doxorubicin-transferrin conjugate; D004317:Doxorubicin; D002374:Catalase; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione
keywords: Anticancer drug conjugate; Glutathione; Reactive oxygen species; Redox homeostasis; Transferrin