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Lymphoma

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

Leukemia volume 19, pages 1977–1984 (2005)Cite this article

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 G1–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.

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Acknowledgements

We thank Drs Numsen Hail, Jr, Ismael J Samudio and Betty L Notzon for critical review of the manuscript. Grant support: Supported in part by grants from the National Institutes of Health (PO1 CA55164 and CA16672) and the Paul and Mary Haas Chair in Genetics (to MA) and a grant from Eli Lilly and Company (to MK).

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Authors and Affiliations

  1. Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    W Zhang, T McQueen, W Schober, M Andreeff & M Konopleva

  2. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Rassidakis

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Correspondence to M Konopleva.

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Zhang, W., McQueen, T., Schober, W. et al. Leukotriene B4 receptor inhibitor LY293111 induces cell cycle arrest and apoptosis in human anaplastic large-cell lymphoma cells via JNK phosphorylation. Leukemia 19, 1977–1984 (2005). https://doi.org/10.1038/sj.leu.2403929

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