Article

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

Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
International journal of hematology (Impact Factor: 1.17). 01/2009; 89(1):45-57. DOI: 10.1007/s12185-008-0226-9
Source: PubMed

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.

0 Bookmarks
 · 
110 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple myeloma (MM) is an incurable B-cell malignancy. Therefore, new targets and drugs are urgently needed to improve patient outcome. Epigenetic aberrations play a crucial role in development and progression in cancer, including MM. To target these aberrations, epigenetic modulating agents, such as DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), are under intense investigation in solid and hematological cancers. A clinical benefit of the use of these agents as single agents and in combination regimens has been suggested based on numerous studies in pre-clinical tumor models, including MM models. The mechanisms of action are not yet fully understood but appear to involve a combination of true epigenetic changes and cytotoxic actions. In addition, the interactions with the BM niche are also affected by epigenetic modulating agents that will further determine the in vivo efficacy and thus patient outcome. A better understanding of the molecular events underlying the anti-tumor activity of the epigenetic drugs will lead to more rational drug combinations. This review focuses on the involvement of epigenetic changes in MM pathogenesis and how the use of DNMTi and HDACi affect the myeloma tumor itself and its interactions with the microenvironment.
    Cancers. 01/2013; 5(2):430-61.
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVES: Histone deacetylase (HDAC) inhibitors are new therapeutic agents, used to treat various types of malignant cancers. In the present study, we investigated the effects of Ky-2, a hybrid-compound HDAC inhibitor, on the growth of mouse myeloma cells. MATERIALS AND METHODS: Myeloma cells, HS-72, P3U1, and mouse normal cells were used in this study. Effect of HDAC inhibitors on cell viability was determined by WST-assay and trypan blue assay. Cell cycle was analyzed using flow cytometer. The expression of cell cycle regulatory and the apoptosis associated proteins were examined by Western blot analysis. Hoechst's staining was used to detect apoptotic cells. RESULTS: Our findings showed that Ky-2 decreased the levels of HDACs, while it enhanced acetylation of histone H3. Myeloma cell proliferation was inhibited by Ky-2 treatment. Interestingly, Ky-2 had no cytotoxic effects on mouse normal cells. Ky-2 treatment induced G1-phase cell cycle arrest and accumulation of a sub-G1 phase population, while western blotting analysis revealed that expressions of the cell cycle-associated proteins were upregulated. Also, Ky-2 enhanced the cleavage of caspase-9 and -3 in myeloma cells, followed by DNA fragmentation. 1 In addition, Ky-2 was not found to induce apoptosis in bcl-2 overexpressing myeloma cells. CONCLUSION: These findings suggest that Ky-2 induces apoptosis via a 4 caspase-dependent cascade and Bcl-2-inhibitable mechanism in myeloma cells.
    Biochemical and Biophysical Research Communications 03/2013; · 2.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: Multiple myeloma (MM) is a B-cell malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow. Although new therapeutic options have been introduced and response rates have improved in recent years, MM still remains incurable and new treatment options are urgently needed. The histone deacetylase inhibitors (HDACi) are a new class of anticancer agents in early clinical development in many malignancies including MM. HDACi target the enzyme histone deacetylase (HDAC) involved in the deacetylation of histone and non-histone cellular proteins that play important roles in epigenetic regulation of gene expression inducing death, apoptosis and cell cycle arrest in cancer cells. Panobinostat (LBH589) is a highly potent HDACi with demonstrated antitumor activities at low nanomolar concentration in several preclinical studies and its clinical efficacy is currently under investigation in several clinical trials. AREA COVERED: In this review the authors discuss the role of HDACs in the regulation of gene expression and the biological mechanisms mediating the anticancer effects of HDACi with particular focus on the recent development of panobinostat as anti-MM agent in preclinical and clinical studies. EXPERT OPINION: As a 'multi-target' drug, panobinostat appears attractive as potential anti-MM therapeutic for its ability to modulate a variety of biological pathways essential in MM biology. This 'multi-target' property of panobinostat may also be one its major shortcomings, and a better understanding of its mechanisms of action and targets will permit to identify the best combination therapies that will ultimately overcome and improve outcomes in MM patients.
    Expert Opinion on Investigational Drugs 03/2012; 21(5):733-47. · 4.74 Impact Factor