title: The novel orally active proteasome inhibitor K-7174 exerts anti-myeloma activity in vitro and in vivo by down-regulating the expression of class I histone deacetylases.
abstract: Bortezomib therapy is now indispensable for multiple myeloma, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. The development of orally active proteasome inhibitors with distinct mechanisms of action is therefore eagerly awaited. Previously, we identified homopiperazine derivatives as a novel class of proteasome inhibitors with a different mode of proteasome binding from bortezomib. In this study, we show that K-7174, one of proteasome inhibitory homopiperazine derivatives, exhibits a therapeutic effect, which is stronger when administered orally than intravenously, without obvious side effects in a murine myeloma model. Moreover, K-7174 kills bortezomib-resistant myeloma cells carrying a β5-subunit mutation in vivo and primary cells from a patient resistant to bortezomib. K-7174 induces transcriptional repression of class I histone deacetylases (HDAC1, -2, and -3) via caspase-8-dependent degradation of Sp1, the most potent transactivator of class I HDAC genes. HDAC1 overexpression ameliorates the cytotoxic effect of K-7174 and abrogates histone hyperacetylation without affecting the accumulation of ubiquitinated proteins in K-7174-treated myeloma cells. Conversely, HDAC inhibitors enhance the activity of K-7174 with an increase in histone acetylation. These results suggest that class I HDACs are critical targets of K-7174-induced cytotoxicity. It is highly anticipated that K-7174 increases the tolerability and convenience of patients by oral administration and has the clinical utility in overcoming bortezomib resistance as a single agent or in combination with HDAC inhibitors.
authors.affiliation: From the Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 and.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kikuchi
authors.affiliation: From the Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamada
authors.affiliation: From the Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koyama
authors.affiliation: From the Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 and.
authors.forename: Taeko
authors.initials: T
authors.lastname: Wada
authors.affiliation: From the Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 and.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nobuyoshi
authors.affiliation: the Division of Hematology, Tochigi Cancer Center, Utsunomiya, Tochigi 320-0834, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Izumi
authors.affiliation: the Division of Hematology, Tochigi Cancer Center, Utsunomiya, Tochigi 320-0834, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Akutsu
authors.affiliation: the Division of Hematology, Tochigi Cancer Center, Utsunomiya, Tochigi 320-0834, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kano
authors.affiliation: From the Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498 and. Electronic address: furuyu@jichi.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology
chemical_list: D000840:Anisoles; D000970:Antineoplastic Agents; D001381:Azepines; D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D011719:Pyrazines; C410337:K 7174; D000069286:Bortezomib; D006655:Histone Deacetylases
keywords: Cancer; Drug Resistance; Histone Deacetylase; Histone Deacetylase Inhibitors; Multiple Myeloma; Proteasome