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01-01-2009 | Original Article

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

Authors: Ken-ichi Kitazoe, Masahiro Abe, Masahiro Hiasa, Asuka Oda, Hiroe Amou, Takeshi Harada, Ayako Nakano, Kyoko Takeuchi, Toshihiro Hashimoto, Shuji Ozaki, Toshio Matsumoto

Published in: International Journal of Hematology | Issue 1/2009

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.

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Title: Valproic acid exerts anti-tumor as well as anti-angiogenic effects on myeloma
Authors: Ken-ichi Kitazoe
Masahiro Abe
Masahiro Hiasa
Asuka Oda
Hiroe Amou
Takeshi Harada
Ayako Nakano
Kyoko Takeuchi
Toshihiro Hashimoto
Shuji Ozaki
Toshio Matsumoto
Publication date: 01-01-2009
Publisher: Springer Japan
Published in: International Journal of Hematology / Issue 1/2009
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI: https://doi.org/10.1007/s12185-008-0226-9

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