title: Imatinib inhibits the expression of SCO2 and FRATAXIN genes that encode mitochondrial proteins in human Bcr-Abl⁺ leukemia cells.
abstract: Imatinib mesylate (IM/Gleevec®), a selective inhibitor of chimeric Bcr-Abl tyrosine kinase, was developed as a first line drug to treat CML and ALL Ph(+) patients. Earlier studies have shown that hemin counteracts the IM-induced cell killing in human K-562 CML cells. In this study, we investigated whether IM disrupts the heme-dependent Cytochrome c Oxidase (COX) Biosynthesis and Assembly Pathway (HDCBAP) in Bcr-Abl(+) and Bcr-Abl(-) cells by affecting the expression of key-genes. Cells were exposed to IM and evaluated at time intervals for cell growth, cell death, expression of various genes by RT-PCR analysis as well as Sco2 mature protein levels by western blot analysis and COX enzymatic activity. IM at 1 μM induced extensive cell growth inhibition and cell death as well as marked suppression of the expression of SCO2 and FRATAXIN (FXN) genes in human K-562 and KU-812 Bcr-Abl(+) CML cells. IM also reduced the protein level of mature Sco2 mitochondrial protein as well as COX activity in these cell lines. However, treatment of human MOLT-4 Bcr-Abl(-) cells with 1μM and even with higher concentrations (4×10(-5)M) of IM neither reduced the expression of SCO2 and FXN genes nor suppressed the protein level of mature Sco2 protein and COX activity. Our findings indicate that SCO2 and FXN genes, involved in HDCBAP, are repressed by IM in human Bcr-Abl(+) CML cells and may represent novel target sites in leukemia therapy.
authors.affiliation: Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki (A.U.TH.), GR-54124 Thessaloniki, Macedonia, Greece.
authors.forename: Lefkothea C
authors.initials: LC
authors.lastname: Papadopoulou
authors.affiliation: Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki (A.U.TH.), GR-54124 Thessaloniki, Macedonia, Greece.
authors.forename: Angeliki V
authors.initials: AV
authors.lastname: Kyriazou
authors.affiliation: Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki (A.U.TH.), GR-54124 Thessaloniki, Macedonia, Greece.
authors.forename: Ioannis D
authors.initials: ID
authors.lastname: Bonovolias
authors.affiliation: Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki (A.U.TH.), GR-54124 Thessaloniki, Macedonia, Greece. Electronic address: tsif@pharm.auth.gr.
authors.forename: Asterios S
authors.initials: AS
authors.lastname: Tsiftsoglou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018832:Molecular Chaperones; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D000096923:Frataxin
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002352:Carrier Proteins; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000096923:Frataxin; C400285:SCO2 protein, human
keywords: Bcr–Abl; COX; FXN; Imatinib; SCO2