title: The novel IKK2 inhibitor LY2409881 potently synergizes with histone deacetylase inhibitors in preclinical models of lymphoma through the downregulation of NF-κB.
abstract: OBJECTIVE
  To evaluate the pharmacologic activity of a novel inhibitor of IκB kinase β (IKK2), LY2409881, in preclinical models of B- and T-cell lymphoma, as a single agent and in combination with histone deacetylase (HDAC) inhibitors.
  
  
  METHODS
  The in vitro activity of LY2409881 was determined using an ATP-based growth inhibition assay and flow cytometric assay of apoptosis in lymphoma cell lines. The in vivo activity of LY2409881 was determined using SCID-beige xenograft mouse model. The mechanism of action was determined using immunoblotting, immuofluorescence, and electrophoretic mobility shift assay. Synergy of LY2409881 with other drugs active in lymphoma was determined by calculating relative risk ratio (RRR) and combination index (CI).
  
  
  RESULTS
  LY2409881 inhibited constitutively activated NF-κB, and caused concentration- and time-dependent growth inhibition and apoptosis in lymphoma cells. In models of diffuse large B-cell lymphoma (DLBCL), the cytotoxicity of LY2409881 correlated with the overall activation status of NF-κB, but not simply in a pattern predicted by the cell-of-origin classification of these cell lines. LY2409881 was safe to mice at three dose levels, 50, 100, and 200 mg/kg, all of which caused significant inhibition of tumor growth. LY2409881 suppressed the activity of the NF-κB subunit p65 in lymphoma cells treated by the HDAC inhibitor romidepsin, underlying a potential mechanism of the marked synergy observed of these two drugs.
  
  
  CONCLUSIONS
  Collectively, these data strongly suggest that targeting the NF-κB pathway in combination with romidepsin could represent a novel and potent regimen for the treatment of B- and T-cell lymphoma.
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. Division of Experimental Therapeutics, Columbia University Medical Center, New York, New York. cd2448@columbia.edu.
authors.forename: Changchun
authors.initials: C
authors.lastname: Deng
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Mark
authors.initials: M
authors.lastname: Lipstein
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Richard
authors.initials: R
authors.lastname: Rodriguez
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Xavier O Jirau
authors.initials: XO
authors.lastname: Serrano
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York.
authors.forename: Christine
authors.initials: C
authors.lastname: McIntosh
authors.affiliation: Department of Statistics, Mailman School of Public Health, Columbia University Medical Center, New York, New York.
authors.forename: Wei-Yann
authors.initials: WY
authors.lastname: Tsai
authors.affiliation: Division of Experimental Therapeutics, Columbia University Medical Center, New York, New York.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Wasmuth
authors.affiliation: Division of Cancer Research, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Susan
authors.initials: S
authors.lastname: Jaken
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. Division of Experimental Therapeutics, Columbia University Medical Center, New York, New York.
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage*; D015398:Signal Transduction; D013876:Thiophenes / Q000008:administration & dosage*
chemical_list: D056572:Histone Deacetylase Inhibitors; C000601358:LY2409881; D016328:NF-kappa B; D011743:Pyrimidines; D013876:Thiophenes; D051550:I-kappa B Kinase; C496560:IKBKB protein, human