title: Lestaurtinib inhibition of the Jak/STAT signaling pathway in hodgkin lymphoma inhibits proliferation and induces apoptosis.
abstract: Standard cytotoxic chemotherapy for Hodgkin Lymphoma (HL) has changed little in 30 years; the treatment for patients with relapsed or refractory disease remains challenging and novel agents are under development. JAK/STAT constitutive activation plays an important role in the pathogenesis of HL. Lestaurtinib is an orally bioavailable multikinase inhibitor that has recently been shown to inhibit JAK2 in myeloproliferative disorders. The potential role of Lestaurtinib in HL therapy is unknown. We have analyzed the effect of Lestaurtinib treatment in five HL cell lines from refractory patients, L-428, L-1236, L-540, HDML-2 and HD-MY-Z. At 48 h, a dose-dependent cell growth inhibition (23%-66% at 300 nM) and apoptotic increment (10%-64% at 300 nM) were observed. Moreover, Lestaurtinib inhibited JAK2, STAT5 and STAT3 phosphorylation and reduced the mRNA expression of its downstream antiapoptotic target Bcl-xL. In addition, we have analyzed the effect of Lestaurtinib treatment in lymph nodes from four classic HL patients. We observed a decrease in cell viability at 24 hours of treatment in three patients (mean decrease of 27% at 300 nM). Our findings provide, for the first time, a molecular rationale for testing JAK2 inhibitors, specifically Lestaurtinib, in HL patients.
authors.affiliation: Human Anatomy Unit, Molecular Oncology and Embryology Laboratory, University of Barcelona Medical School, IDIBAPS, Barcelona, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Diaz
authors.forename: Alfons
authors.initials: A
authors.lastname: Navarro
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferrer
authors.forename: Bernat
authors.initials: B
authors.lastname: Gel
authors.forename: Anna
authors.initials: A
authors.lastname: Gaya
authors.forename: Rosa
authors.initials: R
authors.lastname: Artells
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bellosillo
authors.forename: Mar
authors.initials: M
authors.lastname: Garcia-Garcia
authors.forename: Sergi
authors.initials: S
authors.lastname: Serrano
authors.forename: Antonio
authors.initials: A
authors.lastname: Martínez
authors.forename: Mariano
authors.initials: M
authors.lastname: Monzo
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans; D006689:Hodgkin Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors*
chemical_list: D002227:Carbazoles; D005663:Furans; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; C119379:lestaurtinib; D053612:Janus Kinases