title: Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma.
abstract: Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression ofPPP3CA, a catalytic subunit of calcineurin, was high in advanced patients. Panobinostat degraded PPP3CA, a degradation that should have been induced by inhibition of the chaperone function of heat shock protein 90 (HSP90). Cotreatment with HDAC inhibitors and FK506 led to an enhanced antimyeloma effect with a greater PPP3CA reduction compared with HDAC inhibitors alone both in vitro and in vivo. In addition, this combination treatment efficiently blocked osteoclast formation, which results in osteolytic lesions. The poor response and short PFS duration observed in the bortezomib-containing therapies of patients with highPPP3CAsuggested its relevance to bortezomib resistance. Moreover, bortezomib and HDAC inhibitors synergistically suppressed MM cell viability through PPP3CA inhibition. Our findings underscore the usefulness of calcineurin-targeted therapy in MM patients, including patients who are resistant to bortezomib.
authors.affiliation: Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Ohta
authors.affiliation: Department of Physiology and Cell Biology, Graduate School of Medicine and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Physiology and Cell Biology, Graduate School of Medicine and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Sunamura
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Ishibashi
authors.affiliation: Division of Hematology, Department of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Tamura
authors.affiliation: Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Deguchi
authors.affiliation: Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Maru
authors.affiliation: Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Motoji
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy*; D000077767:Panobinostat; D016559:Tacrolimus / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D019703:Calcineurin; D016559:Tacrolimus