title: The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell             adhesion and induces apoptosis in acute lymphoblastic leukaemia cells.
abstract: Although recent decades have seen an improved cure rate for newly diagnosed             paediatric acute lymphoplastic leukaemia (ALL), the treatment options for adult             ALL, T-cell ALL (T-ALL) and relapsed disease remain poor. We have developed a             novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds and established their             anticancer efficacy in a variety of human tumour cell types. Here, we demonstrate             that PBOX-15 inhibits cell growth, and induces G2/M cell cycle arrest and apoptosis             in both T-ALL and B-cell ALL (B-ALL) cells. In addition, prior to PBOX-15-induced             apoptosis, PBOX-15 decreases ALL cell adhesion, spreading and migration. Concurrently,             PBOX-15 differentially down-regulates β1-, β2- and α4-integrin expression in ALL             cells and significantly decreases integrin-mediated cell attachment. PBOX-15 interferes             with the lateral mobility and clustering of integrins in both B-ALL and T-ALL             cells. These data suggest that PBOX-15 is not only effective in inducing apoptosis             in ALL cells, but also has the potential to disrupt integrin-mediated adhesion             of malignant lymphocytes, which represents a novel avenue for regulating leukaemic             cell homing and migration.
authors.affiliation: Department of Haematology, Trinity College, Dublin, Ireland.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lysaght
authors.forename: Navin K
authors.initials: NK
authors.lastname: Verma
authors.forename: Elaina N
authors.initials: EN
authors.lastname: Maginn
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Ryan
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: D Clive
authors.initials: DC
authors.lastname: Williams
authors.forename: Paul V
authors.initials: PV
authors.lastname: Browne
authors.forename: Mark P
authors.initials: MP
authors.lastname: Lawler
authors.forename: Anthony M
authors.initials: AM
authors.lastname: McElligott
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects*; D010077:Oxazepines / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C514160:4-acetoxy-5-(1-(naphthyl))naphtho(2,3-b)pyrrolo(2,1-d)(1,4)oxazepine; D016023:Integrins; D010077:Oxazepines; D011758:Pyrroles