title: Valproic acid exerts anti-tumor as well as anti-angiogenic effects on myeloma.
abstract: Multiple myeloma is still an incurable disease, most commonly occurring in the elderly. The myeloma-induced bone marrow microenvironment protects myeloma cells from drug-induced apoptosis. Therefore, the development of novel and tolerable therapeutic alternatives to overcome the drug resistance is an important clinical issue. Valproic acid (VPA), a safe and widely used anti-epileptic agent, is revisited as a class I- and IIa-specific histone deacetylase inhibitor. In the present study, we evaluated the effect as well as a mechanism of actions of VPA on myeloma cell growth and survival, with special reference to the myeloma-induced bone marrow microenvironment. VPA at therapeutic concentrations for epilepsy induced cell death in primary CD138-positive myeloma cells as well as myeloma cell lines, but not in CD138-negative bone marrow cells. VPA suppressed osteoclastogenesis as well as osteoclast-mediated myeloma cell growth. VPA also inhibited vascular tubule formation enhanced by co-cultures of myeloma cells and osteoclasts in concert with thalidomide. In addition, VPA induced both caspase-dependent and -independent cell death in myeloma cells, and potentiated the anti-myeloma effects of melphalan and dexamethasone. Collectively, VPA is suggested to exert multi-factorial anti-myeloma actions, and may serve as a safe adjuvant to be included in conventional chemotherapies against myeloma.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Kitazoe
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. masabe@clin.med.tokushima-u.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Orthodontics, Graduate School of Dental Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiasa
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Oda
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Amou
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakano
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Division of Transfusion Medicine, Tokushima University Hospital, Tokushima, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ozaki
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001853:Bone Marrow / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010010:Osteoclasts / Q000473:pathology; D013792:Thalidomide / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D013792:Thalidomide; D014635:Valproic Acid