International Journal of Hematology

, Volume 89, Issue 1, pp 45–57

Valproic acid exerts anti-tumor as well as anti-angiogenic effects on myeloma

  • Ken-ichi Kitazoe
  • Masahiro Abe
  • Masahiro Hiasa
  • Asuka Oda
  • Hiroe Amou
  • Takeshi Harada
  • Ayako Nakano
  • Kyoko Takeuchi
  • Toshihiro Hashimoto
  • Shuji Ozaki
  • Toshio Matsumoto
Original Article

DOI: 10.1007/s12185-008-0226-9

Cite this article as:
Kitazoe, K., Abe, M., Hiasa, M. et al. Int J Hematol (2009) 89: 45. doi:10.1007/s12185-008-0226-9

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.

Keywords

Valproic acid Myeloma Osteoclast Angiogenesis Apoptosis 

Copyright information

© The Japanese Society of Hematology 2008

Authors and Affiliations

  • Ken-ichi Kitazoe
    • 1
  • Masahiro Abe
    • 1
  • Masahiro Hiasa
    • 2
  • Asuka Oda
    • 1
  • Hiroe Amou
    • 1
  • Takeshi Harada
    • 1
  • Ayako Nakano
    • 1
  • Kyoko Takeuchi
    • 1
  • Toshihiro Hashimoto
    • 1
  • Shuji Ozaki
    • 3
  • Toshio Matsumoto
    • 1
  1. 1.Department of Medicine and Bioregulatory Sciences, Graduate School of Medical SciencesUniversity of TokushimaTokushimaJapan
  2. 2.Department of Orthodontics, Graduate School of Dental SciencesUniversity of TokushimaTokushimaJapan
  3. 3.Division of Transfusion MedicineTokushima University HospitalTokushimaJapan

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