title: Comparative endothelial profiling of doxorubicin and daunorubicin in cultured endothelial cells.
abstract: Although anthracycline antibiotics have been successfully used for nearly half a century in the treatment of various malignancies, their use is limited by their cardiac and vascular toxicities, and the mechanisms of these toxicities are still not entirely clear. Herein, we comprehensively characterized cytotoxic effects of two structurally related anthracyclines, doxorubicin and daunorubicin. In nanomolar concentrations, both drugs induced DNA damage and increased nuclear area that were associated with their accumulation in the nucleus (doxorubicin ⩾50 nM and daunorubicin ⩾25 nM) as evidence by Raman microspectroscopy at 3820-4245 cm(-1). At low micromolar concentrations, doxorubicin (⩾5 μM) and daunorubicin (⩾1 μM) increased the generation of reactive oxygen species, decreased intracellular reduced glutathione, induced an alteration in endothelial elasticity and caused a reorganization of the F-actin cytoskeleton. In isolated mouse aortic rings, doxorubicin (⩾50 μM) was less potent than daunorubicin (⩾5 μM) in impairing the endothelium-dependent response. In summary, using a comprehensive endothelial profiling approach, we demonstrated clear-cut differences in the potencies to induce endotheliotoxic responses for two structurally similar chemotherapeutics, at a nuclear, cytosolic and membrane levels. Furthermore, our results suggest that the differences in the endothelial toxicities of doxorubicin and daunorubicin are linked to differences in their nuclear accumulation and the DNA damage-triggered response of the endothelium.
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wojcik
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Buczek
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Majzner
authors.affiliation: Department of Physics of Nanostructures and Nanotechnology, Jagiellonian University, Reymonta 4, 30-059 Krakow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kolodziejczyk
authors.affiliation: Department of Experimental Physics of Complex Systems, The H. Niewodniczanski Institute of Nuclear Physics Polish Academy of Sciences, 31-342 Krakow, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Miszczyk
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Kaczara
authors.affiliation: Department of Experimental Physics of Complex Systems, The H. Niewodniczanski Institute of Nuclear Physics Polish Academy of Sciences, 31-342 Krakow, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kwiatek
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Baranska
authors.affiliation: Department of Physics of Nanostructures and Nanotechnology, Jagiellonian University, Reymonta 4, 30-059 Krakow, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Szymonski
authors.affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University, Medical College, Grzegorzecka 16, 31-531 Krakow, Poland. Electronic address: stefan.chlopicki@jcet.eu.
authors.forename: Stefan
authors.initials: S
authors.lastname: Chlopicki
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001013:Aorta, Thoracic; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D003630:Daunorubicin / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D042783:Endothelial Cells / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D066298:In Vitro Techniques; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000199:Actins; D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D020169:Caspases; D003630:Daunorubicin
keywords: Cytotoxicity; Daunorubicin; Doxorubicin; Endothelium; High-content screening