title: Cytotoxicity of quinone drugs on highly proliferative human leukemia T cells: reactive oxygen species generation and inactive shortened SOD1 isoform implications.
abstract: Drugs containing the quinone group were tested on hyperproliferative leukemia T cells (HLTC: Jhp and Jws) and parental Jurkat cells. Doxorubicin, menadione and adaphostin produced different effects on these cell lines. Rapid doxorubicin-induced cell death in Jurkat cells was mediated by caspase activation. Doxorubicin-induced cell death of HLTCs was delayed due to the absence of caspase-3 and -8 expression. Delayed HLTC cell death was mediated and triggered by the generation of reactive oxygen species (ROS). Other drugs containing quinone groups, such as menadione and adaphostin, were also tested on HLTC and both were toxic by a caspase-independent mechanism. The toxicity of these drugs correlated with the generation of the superoxide anion, which increased and was more effective in HLTCs than in parental Jurkat cells. Accordingly, SOD1 activity was much lower in HLTCs than in Jurkat cells. This lower SOD1 activity in HLTCs was associated not only with the absence of the wild-type (16 kDa) SOD1 monomer but also with the presence of a shortened (14 kDa) SOD1 monomer isoform. Moreover, the cytotoxicity of drugs containing the quinone group was prevented by incubation with manganese(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), a cell-permeable superoxide dismutase mimetic and a potent inhibitor of oxidation. These findings could explain the sensitivity of HLTCs to drugs containing the quinone group using a mechanism dependent on oxidative stress. These observations can also be useful to target hyperproliferative leukemias that are resistant to the classical caspase-dependent apoptotic pathway.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza 50009, Spain.
authors.forename: Juan Ignacio
authors.initials: JI
authors.lastname: Aguiló
authors.forename: María
authors.initials: M
authors.lastname: Iturralde
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Monleón
authors.forename: Pedro
authors.initials: P
authors.lastname: Iñarrea
authors.forename: Julián
authors.initials: J
authors.lastname: Pardo
authors.forename: María José
authors.initials: MJ
authors.lastname: Martínez-Lorenzo
authors.forename: Alberto
authors.initials: A
authors.lastname: Anel
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Alava
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D019169:Jurkat Cells; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D011809:Quinones / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D000970:Antineoplastic Agents; D007527:Isoenzymes; D009363:Neoplasm Proteins; D011809:Quinones; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D004317:Doxorubicin; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020169:Caspases