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

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

doi:10.3892/ijo.2012.1688

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

Authors:
- 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
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Affiliations: Department of Haematology, John Durkan Leukaemia Laboratories, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland, Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland, European Research Centre for Drug Discovery and Development, University of Siena, Italy, School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
Published online on: November 6, 2012 https://doi.org/10.3892/ijo.2012.1688
Pages: 239-246

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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.

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