Leukotriene B4 receptor inhibitor LY293111 induces cell cycle arrest and apoptosis in human anaplastic large-cell lymphoma cells via JNK phosphorylation

Leukemia. 2005 Nov;19(11):1977-84. doi: 10.1038/sj.leu.2403929.


Anaplastic large-cell lymphoma (ALCL) is a heterogeneous lymphoma category in which a subset of cases carry the t(2;5)(p23;q35) or variant translocations resulting in overexpression of anaplastic lymphoma kinase (ALK). LY293111 (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]-propoxy]-phenoxy] benzoic acid sodium salt) is a leukotriene B4 receptor antagonist, which was found to be safe and tolerable in Phase I clinical trials. In this study, we investigated the potential therapeutic effects and mechanisms of action of LY293111 in ALCL cell lines. LY293111 inhibited proliferation of both ALK(+) and ALK(-) ALCL cell in a dose-dependent fashion and induced complete G(1)-S cell cycle arrest, which was accompanied by upregulation of p27 and downregulation of cyclin E. Pretreatment with LY293111 for 4 h resulted in profound inhibition of serum-induced phosphorylation of extracellular-regulated kinases-1 and 2 and Akt and a concomitant increase in the phosphorylation of the stress-activated kinase c-jun N-terminal kinases (JNK). Simultaneously, LY293111 induced caspase-dependent apoptosis via activation of the intrinsic pathway, including early loss of mitochondrial inner transmembrane potential and the production of reactive oxygen species (ROS), cleavage of caspases-9, -3, poly ADP-ribose polymerase (PARP) and X-linked inhibitor of apoptosis. The phospho-JNK inhibitor SP600125 partially protected Sup-M2 cells from LY293111-induced apoptosis, PARP cleavage and ROS generation, suggesting a role for JNK in LY293111-induced cell death. These results warrant further studies of LY293111 in ALCL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects*
  • Benzoates / pharmacology*
  • Cell Cycle / drug effects*
  • Cell Cycle Proteins / biosynthesis
  • Cyclin E / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p27
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology*
  • MAP Kinase Kinase 4
  • Membrane Potentials
  • Mitochondria / physiology
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Phosphorylation
  • Reactive Oxygen Species
  • Receptors, Leukotriene B4
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / biosynthesis
  • Up-Regulation


  • Benzoates
  • Cell Cycle Proteins
  • Cyclin E
  • LY 293111
  • Reactive Oxygen Species
  • Receptors, Leukotriene B4
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases