title: Troglitazone overcomes doxorubicin-resistance in resistant K562 leukemia cells.
abstract: Human myeloid leukemia cells become resistant to doxorubicin (DOX) treatment and this resistance is correlated with an increased glyoxalase 1 (GLO1) expression. Troglitazone (TRG) is an anti-diabetic thiazolidinedione drug previously used to treat insulin-resistance in Type 2 diabetes. We previously showed that TRG down regulates GLO1 gene expression in a number of cell types and reasoned that TRG might be a useful adjunct therapy to overcome DOX resistance. Here we show that TRG treatment overcomes the resistance to DOX in the DOX-resistant K562 human leukemia cells. Higher doses of TRG were found to alter histone H3:H2B ratios with a decreased ratio in DOX-sensitive and increased ratio in DOX-resistant lines. Furthermore, phosphorylated H3 was seen in DOX-resistant but not in DOX-sensitive cells. We conclude that the downstream effect of TRG in DOX-resistant cells may be interference with normal cell cycle events leading to genomic instability. Our data suggest that TRG may be a useful adjunct therapy in circumventing drug resistance in K562 leukemia cells.
authors.affiliation: Department of Anatomy, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Davies
authors.forename: William J
authors.initials: WJ
authors.lastname: Roesler
authors.forename: Bernhard H J
authors.initials: BH
authors.lastname: Juurlink
authors.forename: Troy A A
authors.initials: TA
authors.lastname: Harkness
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D007791:Lactoylglutathione Lyase / Q000235:genetics; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D000970:Antineoplastic Agents; D002839:Chromans; D045162:Thiazolidinediones; D004317:Doxorubicin; D007791:Lactoylglutathione Lyase; D000077288:Troglitazone