title: Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma.
abstract: Histone deacetylase (HDAC) enzymatic activity has been linked to the transcription of DNA in cancers including multiple myeloma (MM). Therefore, HDAC inhibitors used alone and in combination are being actively studied as novel therapies in MM. In the present study, we investigated the preclinical activity of ACY-1215, an HDAC6-selective inhibitor, alone and in combination with bortezomib in MM. Low doses of ACY-1215 combined with bortezomib triggered synergistic anti-MM activity, resulting in protracted endoplasmic reticulum stress and apoptosis via activation of caspase-3, caspase-8, and caspase-9 and poly (ADP) ribosome polymerase. In vivo, the anti-MM activity of ACY-1215 in combination with bortezomib was confirmed using 2 different xenograft SCID mouse models: human MM injected subcutaneously (the plasmacytoma model) and luciferase-expressing human MM injected intravenously (the disseminated MM model). Tumor growth was significantly delayed and overall survival was significantly prolonged in animals treated with the combination therapy. Pharmacokinetic data showed peak plasma levels of ACY-1215 at 4 hours after treatment coincident with an increase in acetylated α-tubulin, a marker of HDAC6 inhibition, by immunohistochemistry and Western blot analysis. These studies provide preclinical rationale for acetylated α-tubulin use as a pharmacodynamic biomarker in future clinical trials.
authors.affiliation: Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Tseng
authors.forename: David
authors.initials: D
authors.lastname: Tamang
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Matthew
authors.initials: M
authors.lastname: Jarpe
authors.forename: John H
authors.initials: JH
authors.lastname: van Duzer
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: Walter C
authors.initials: WC
authors.lastname: Ogier
authors.forename: Diana
authors.initials: D
authors.lastname: Cirstea
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.forename: Homare
authors.initials: H
authors.lastname: Eda
authors.forename: Tyler
authors.initials: T
authors.lastname: Scullen
authors.forename: Miriam
authors.initials: M
authors.lastname: Canavese
authors.forename: James
authors.initials: J
authors.lastname: Bradner
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Simon S
authors.initials: SS
authors.lastname: Jones
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010954:Plasmacytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011719:Pyrazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000069286:Bortezomib; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C572255:ricolinostat