Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma

• Published in: Blood Vol. 119; no. 11; pp. 2579 - 2589
• Main Authors: Santo, Loredana, Hideshima, Teru, Kung, Andrew L., Tseng, Jen-Chieh, Tamang, David, Yang, Min, Jarpe, Matthew, van Duzer, John H., Mazitschek, Ralph, Ogier, Walter C., Cirstea, Diana, Rodig, Scott, Eda, Homare, Scullen, Tyler, Canavese, Miriam, Bradner, James, Anderson, Kenneth C., Jones, Simon S., Raje, Noopur
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.03.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Boronic Acids - pharmacology; Bortezomib; Cell Proliferation - drug effects; Drug Synergism; Endoplasmic Reticulum Stress - drug effects; Fluorescent Antibody Technique; Hematologic and hematopoietic diseases; Histone Deacetylase 6; Histone Deacetylase Inhibitors - pharmacokinetics; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - pharmacokinetics; Hydroxamic Acids - pharmacology; Immunodeficiencies. Immunoglobulinopathies; Immunoenzyme Techniques; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoid Neoplasia; Male; Medical sciences; Mice; Mice, SCID; Plasmacytoma - drug therapy; Plasmacytoma - metabolism; Plasmacytoma - pathology; Pyrazines - pharmacology; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Real-Time Polymerase Chain Reaction; RNA, Messenger - genetics; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Antineoplastic agent; Immunopathology; Drug combination; Pharmacodynamics; Bortezomib; Hematology; Histone deacetylase 6; Malignant hemopathy; Myeloma; Biological activity; Immunoglobulinopathy; Analog; Proteasome inhibitor; Lymphoproliferative syndrome; Dipeptides; Pharmacokinetics; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-10-387365

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.