title: Leukotriene B4 receptor inhibitor LY293111 induces cell cycle arrest and apoptosis in human anaplastic large-cell lymphoma cells via JNK phosphorylation.
abstract: 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.
authors.affiliation: Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: McQueen
authors.forename: W
authors.initials: W
authors.lastname: Schober
authors.forename: G
authors.initials: G
authors.lastname: Rassidakis
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
authors.forename: M
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D019927:Cyclin E / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D048670:MAP Kinase Kinase 4; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D001565:Benzoates; D018797:Cell Cycle Proteins; D019927:Cyclin E; C094099:LY 293111; D017382:Reactive Oxygen Species; D018102:Receptors, Leukotriene B4; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases