The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

Joanne Lysaght, Navin K Verma, Elaina N Maginn, Jacqueline M Ryan, Giuseppe Campiani, Daniela M Zisterer, D Clive Williams, Paul V Browne, Mark P Lawler, Anthony M McElligott, Mark Lawler

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)239-46
Number of pages8
JournalInternational journal of oncology
Volume42
Issue number1
DOIs
Publication statusPublished - Jan 2013

Keywords

  • Apoptosis
  • Blotting, Western
  • Cell Adhesion
  • Cell Cycle Checkpoints
  • Cell Movement
  • Cell Proliferation
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Integrins
  • Microtubules
  • Oxazepines
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Pyrroles
  • Tumor Cells, Cultured

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