title: The combination of HDAC and aminopeptidase inhibitors is highly synergistic in myeloma and leads to disruption of the NFκB signalling pathway.
abstract: There is a growing body of evidence supporting the use of epigenetic therapies in the treatment of multiple myeloma. We show the novel HDAC inhibitor CHR-3996 induces apoptosis in myeloma cells at concentrations in the nanomolar range and with apoptosis mediated by p53 and caspase pathways. In addition, HDAC inhibitors are highly synergistic, both in vitro and in vivo, with the aminopeptidase inhibitor tosedostat (CHR-2797). We demonstrate that the basis for this synergy is a consequence of changes in the levels of NFκB regulators BIRC3/cIAP2, A20, CYLD, and IκB, which were markedly affected by the combination. When co-administered the HDAC and aminopeptidase inhibitors caused rapid nuclear translocation of NFκB family members p65 and p52, following activation of both canonical and non-canonical NFκB signalling pathways. The subsequent up-regulation of inhibitors of NFκB activation (most significantly BIRC3/cIAP2) turned off the cytoprotective effects of the NFκB signalling response in a negative feedback loop. These results provide a rationale for combining HDAC and aminopeptidase inhibitors clinically for the treatment of myeloma patients and support the disruption of the NFκB signalling pathway as a therapeutic strategy.
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research, London, UK.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Smith
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research, London, UK.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research, London, UK.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research, London, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Davenport
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research, London, UK.
authors.forename: Lauren I
authors.initials: LI
authors.lastname: Aronson
authors.affiliation: Chroma Therapeutics Ltd., Abingdon, UK.
authors.forename: David
authors.initials: D
authors.lastname: Krige
authors.affiliation: Chroma Therapeutics Ltd., Abingdon, UK.
authors.forename: Leon
authors.initials: L
authors.lastname: Hooftman
authors.affiliation: Chroma Therapeutics Ltd., Abingdon, UK.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Drummond
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research, London, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, Cancer Therapeutics and Clinical Studies, The Institute of Cancer Research, London, UK.
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053961:Azabicyclo Compounds / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology*; D016328:NF-kappa B / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D011743:Pyrimidines / Q000008:administration & dosage*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C555225:2-(6-(((6-fluoroquinolin-2-yl)methyl)amino)bicyclo(3.1.0)hex-3-yl)-N-hydroxypyrimidine-5-carboxamide; D053961:Azabicyclo Compounds; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; D011743:Pyrimidines; D000626:Aminopeptidases; C531970:tosedostat; D005998:Glycine
keywords: HDAC inhibitor; NFκB; aminopeptidase inhibitor; myeloma