title: Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor ACY-1215 and Bortezomib Is Synergistic in Lymphoma.
abstract: OBJECTIVE
  Pan-class histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. HDAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for degradation. We investigated the mechanism and therapeutic impact of the selective HDAC6 inhibitor ACY-1215 alone and in combination with bortezomib in preclinical models of lymphoma.
  
  
  METHODS
  Concentration-effect relationships were defined for ACY-1215 across 16 lymphoma cell lines and for synergy with bortezomib. Mechanism was interrogated by immunoblot and flow cytometry. An in vivo xenograft model of DLBCL was used to confirm in vitro findings. A collection of primary lymphoma samples were surveyed for markers of the unfolded protein response (UPR).
  
  
  RESULTS
  Concentration-effect relationships defined maximal cytotoxicity at 48 hours with IC50 values ranging from 0.9 to 4.7 μmol/L. Strong synergy was observed in combination with bortezomib. Treatment with ACY-1215 led to inhibition of the aggresome evidenced by acetylated α-tubulin and accumulated polyubiquitinated proteins and upregulation of the UPR. All pharmacodynamic effects were enhanced with the addition of bortezomib. Findings were validated in vivo where mice treated with the combination demonstrated significant tumor growth delay and prolonged overall survival. Evaluation of a collection of primary lymphoma samples for markers of the UPR revealed increased HDAC6, GRP78, and XBP-1 expression as compared with reactive lymphoid tissue.
  
  
  CONCLUSIONS
  These data are the first results to demonstrate that dual targeting of protein degradation pathways represents an innovative and rational approach for the treatment of lymphoma.
authors.affiliation: Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, New York. jea2149@columbia.edu.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Amengual
authors.affiliation: Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Paul
authors.initials: P
authors.lastname: Johannet
authors.affiliation: Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Lombardo
authors.affiliation: Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Kelly
authors.initials: K
authors.lastname: Zullo
authors.affiliation: Division of Hematopathology, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hoehn
authors.affiliation: Division of Hematopathology, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Luigi
authors.initials: L
authors.lastname: Scotto
authors.affiliation: Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jirau-Serrano
authors.affiliation: Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Dejan
authors.initials: D
authors.lastname: Radeski
authors.affiliation: Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Heinen
authors.affiliation: Division of Clinical Pathology, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Division of Clinical Pathology, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Acetylon Pharmaceuticals, Inc., Boston, Massachusetts.
authors.forename: Simon
authors.initials: S
authors.lastname: Jones
authors.affiliation: Center for Lymphoid Malignancies, Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D059748:Proteolysis; D011743:Pyrimidines / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D056572:Histone Deacetylase Inhibitors; C000717248:Hspa5 protein, mouse; D006877:Hydroxamic Acids; D011743:Pyrimidines; D014404:Tubulin; D000069286:Bortezomib; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C572255:ricolinostat