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.
SourceAvailable from: Ken Maes[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.06/2013; 5(2):430-61. DOI:10.3390/cancers5020430
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ABSTRACT: Valproic acid (VPA), a well-known anti-epilepsy drug, has been currently applied as a novel anti-cancer agent in the investigation of cancer drug development. VPA can modulate multiple cell processes and tumor suppression by its involvement in various signaling pathways. VPA functions as a tumor suppressor against various cancers, mainly by acting as a histone deacetylase (HDAC) inhibitor. However, in certain types of cancers, VPA plays a different role by activating HDACs and reducing histone acetylation. Moreover, VPA was recently found involved in the regulation of Notch signaling. This Notch signaling plays a critical role in certain cancers and has dual functions, acting as either as a tumor suppressor in some cancers or an oncogene in some others. VPA up-regulates Notch signaling and subsequently reduces tumor growth in most investigated cancer cells, but is also found to down-regulate Notch signaling in hepatocelluler cancer cells. The newest findings showing that VPA up-regulates the expression of certain G protein-coupled receptors (GPCRs) provides a promising strategy to dramatically enhance anti-cancer efficacy when VPA is combined with receptor-targeted cytotoxic conjugates. VPA itself has few side effects and displays broad anti-cancer activity in many cancers, but its effect is very limited. Thus, VPA was used as an ideal adjuvant in combination with other anti-cancer agents such as celecoxib, bortezomib, irinotecan (CPT-11), paclitaxel, rapamycin (mTOR) inhibitor RAD001, clofarabine, lovastatin and gemcitabine. These agents, in combination and at lower doses, effectively augment synergistical effects on many cancers such as leukemia, neuroblastoma, breast cancer and prostate cancer glioblastoma, with many cases under clinical investigation. *Valproic Acid: Pharmacology, Mechanisms of Action and Clinical Implications, 01/2012: pages 1-39; Nova Science Publishers.
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ABSTRACT: Introduction: Bone disease is present in the majority of patients with multiple myeloma and can seriously affect quality of life and survival rate. In addition to suppression of osteoclastogenesis, there have been developments made in terms of the therapeutic agents available, such as novel immunomodulating agents, proteasome and receptor activator of nuclear factor κB ligand inhibitors. Areas covered: Areas covered include in vitro, in vivo and clinical evidence was collected using MEDLINE® (1950 - May 2014), EMBASE (1980 - May 2014) and Google Scholar (1980 - May 2014) databases. Expert opinion: Bisphosphonates are the mainstay of myeloma bone disease treatment. Oral clodronate and intravenous pamidronate and zoledronic acid are currently used drugs and seem to have comparable results in preventing skeletal-related events of the disease. Zoledronate can also have survival benefits and based on the available evidence is the superior bisphosphonate; however, its side effects have to be monitored. Denosumab had comparable results with zoledronate on myeloma bone disease treatment; its use has not been completely proven yet. There is an expanding set of drugs, proteasome inhibitors, under investigation with great potential to reduce the negative effects of myeloma cells on bone. Future clinical studies should compare both the catabolic and anabolic effects of these agents on bone.Expert Opinion on Biological Therapy 11/2014; 15(2):1-18. DOI:10.1517/14712598.2015.978853 · 3.65 Impact Factor