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: 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
• Journal: International journal of oncology (Int J Oncol) Vol. 42 Issue 1 Pg. 239-46 (Jan 2013) ISSN: 1791-2423 [Electronic] Greece
• PMID: 23135704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-acetoxy-5-(1-(naphthyl))naphtho(2,3-b)pyrrolo(2,1-d)(1,4)oxazepine
• Integrins
• Oxazepines
• Pyrroles

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Cell Adhesion (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Flow Cytometry
• Fluorescent Antibody Technique
• Humans
• Integrins (metabolism)
• Microtubules (drug effects)
• Oxazepines (pharmacology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism, pathology)
• Pyrroles (pharmacology)
• Tumor Cells, Cultured