title: The atypical pattern of cell death in B16F10 melanoma cells treated with TNP-470.
abstract: TNP-470 is an acknowledged anti-angiogenic factor, and was studied clinically as an anti-cancer drug. We previously reported on an additional property of this molecule: the intracellular generation of reactive oxygen species in B16F10 melanoma cells. We showed that a massive generation of ROS occurred in the first few hours after treatment with TNP-470 and that this event was critical to subsequent cell death. In this study, we analyzed the process of cell death and noticed an atypical pattern of death markers. Some of these, such as DNA fragmentation or condensation of chromatin, were characteristic for programmed cell death, while others (the lack of phosphatidylserine flip-flop but permeability to propidium iodide, the maintenance of adhesion to the substratum, no change in mitochondrial transmembrane potential, no effect of the panspecific caspase inhibitor) rather suggested a necrotic outcome. We concluded that TNP-470 induced at least some pathways of programmed cell death. However, increasing damage to critical cell functions appears to cause a rapid switch into the necrotic mode. Our data is similar to that in other reports describing the action of ROS-generating agents. We hypothesize that this rapid programmed cell death/necrosis switch is a common scenario following free radical stress.
authors.affiliation: Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, Medical University of Gdańsk, Debinki 1, Gdańsk, Poland. marcin.okroj@med.lu.se
authors.forename: Marcin
authors.initials: M
authors.lastname: Okrój
authors.forename: Dorota
authors.initials: D
authors.lastname: Stawikowska
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Słomińska
authors.forename: Andrzej
authors.initials: A
authors.lastname: Myśliwski
authors.forename: Jacek
authors.initials: J
authors.lastname: Bigda
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D004273:DNA, Neoplasm / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011419:Propidium / Q000378:metabolism; D012717:Sesquiterpenes / Q000493:pharmacokinetics*; D020298:U937 Cells
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D004273:DNA, Neoplasm; D012717:Sesquiterpenes; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D011419:Propidium; D000255:Adenosine Triphosphate; D016650:Fluorescein-5-isothiocyanate; D000077609:O-(Chloroacetylcarbamoyl)fumagillol