title: Benfluron Induces Cell Cycle Arrest, Apoptosis and Activation of p53 Pathway in MOLT-4 Leukemic Cells.
abstract: The aim of our study was to determine the effect of potential anti-tumour agent benfluron on human leukemic cells MOLT-4 and elucidate the molecular mechanisms of response of tumour cells to this chemotherapeutic agent. It has been shown that the mechanisms of action of benfluron are complex, but the molecular pathways of the cytostatic effect have remained unknown and the present study contributes to their elucidation. In this work, benfluron reduced viability of the treated cells and induced caspase-mediated apoptosis. The programmed cell death was associated with activation of caspases 8, 9 and 3/7. Moreover, exposure of cells to benfluron resulted in accumulation of the cells primarily in late S and G2/M phases. The changes in the levels of key proteins show that benfluron provoked activation of p53 and induced phosphorylation of p53 on serine 15 and serine 392. The application of benfluron led to phosphorylation of Chk1 on serine 345 and phosphorylation of Chk2 on threonine 68 in the treated cells. Higher doses of benfluron caused phosphorylation of ERK1/2 on threonine 202 and tyrosine 204, whereas JNK and p38 kinases were not activated. In conclusion, benfluron induces apoptosis, cell cycle arrest in late S and G2/M phases, and activates various signalling pathways of the DNA damage response.
authors.affiliation: Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Králové, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Seifrtová
authors.affiliation: Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Czech Republic.
authors.forename: T
authors.initials: T
authors.lastname: Cochlarová
authors.affiliation: Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Králové, Czech Republic.
authors.forename: R
authors.initials: R
authors.lastname: Havelek
authors.affiliation: Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Králové, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Řezáčová
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D005449:Fluorenes / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D005449:Fluorenes; D016159:Tumor Suppressor Protein p53; C034234:VUFB 13468; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3