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.
"TNF-α is activated from inactive pro- TNF-α by TACE, and released from a cell surface. It directly stimulates MM cell growth and survival as well as creates pathological microenvironment with enhanced ostesclastogenesis and angiogeneisis –. TNF-α activates NF-κB in MM cells, which leads to enhance the expression of c-FLIP, a potent inhibitor for caspase8 activation, to attenuate the death receptor-mediated apoptotic pathway , . Therefore, the suppression of TNF-α activation by TACE inhibition may also help TRAIL-induced MM cell death. "
[Show abstract][Hide abstract] ABSTRACT: TNF-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) selectively induces apoptosis in various cancer cells including myeloma (MM) cells. However, the susceptibility of MM cells to TRAIL is largely low in most of MM cells by yet largely unknown mechanisms. Because TNF-α converting enzyme (TACE) can cleave some TNF receptor family members, in the present study we explored the roles of proteolytic modulation by TACE in TRAIL receptor expression and TRAIL-mediated cytotoxicity in MM cells.
MM cells preferentially expressed death receptor 4 (DR4) but not DR5 on their surface along with TACE. Conditioned media from RPMI8226 and U266 cells contained a soluble form of DR4. The DR4 levels in these conditioned media were reduced by TACE inhibition by the TACE inhibitor TAPI-0 as well as TACE siRNA. Conversely, the TACE inhibition restored surface levels of DR4 but not DR5 in these cells without affecting DR4 mRNA levels. The TACE inhibition was able to restore cell surface DR4 expression in MM cells even in the presence of bone marrow stromal cells or osteoclasts, and enhanced the cytotoxic effects of recombinant TRAIL and an agonistic antibody against DR4 on MM cells.
These results demonstrate that MM cells post-translationally down-modulate the cell surface expression of DR4 through ectodomain shedding by endogenous TACE, and that TACE inhibition is able to restore cell surface DR4 levels and the susceptibility of MM cells to TRAIL or an agonistic antibody against DR4. Thus, TACE may protect MM cells from TRAIL-mediated death through down-modulation of cell-surface DR4. It can be envisaged that TACE inhibition augments clinical efficacy of TRAIL-based immunotherapy against MM, which eventually becomes resistant to the present therapeutic modalities.
PLoS ONE 02/2012; 7(2):e31594. DOI:10.1371/journal.pone.0031594 · 3.23 Impact Factor
"In the recent couple of decades, VPA has displayed its wide anti-cancer ability in many types of cancers such as cervical cancer , prostate cancer    , neuroblastoma  , thyroid cancer , myeloma , colonrecal cancer , glioma  , leukemia , and breast cancer . VPA could induce DNA damage, cell cycle arrest, cell apoptosis and differentiation, suppress cell proliferation, angiogenesis, tumor metastasis     , and modulate cellular senescence  . "
[Show abstract][Hide abstract] 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.
"; Mitsiades et al, 2004, 2003), NVP- LAQ824 (Catley et al, 2003), depsipeptide (Khan et al, 2004), KD5170 (Feng et al, 2007), valproic acid (Neri et al, 2008; Kitazoe et al, 2009), LBH589 (Maiso et al, 2006) and JNJ- 26481585 (Deleu et al, 2009a,b). Our group has recently evaluated the effect of resminostat in MM (Mandl-Weber et al, 2010). "
[Show abstract][Hide abstract] ABSTRACT: In view of the fact that histone deacetylases (HDACs) are promising targets for myeloma therapy, we investigated the effects of the HDAC inhibitor CR2408 on multiple myeloma (MM) cells in vitro. CR2408 is a direct pan-HDAC inhibitor and inhibits all known 11 HDACs with a 50% inhibitory concentration (IC(50) ) of 12 nmol/l (HDAC 6) to 520 nmol/l (HDAC 8). Correspondingly, CR2408 induces hyperacetylation of histone H4, inhibits cell growth and strongly induces apoptosis (IC(50) =0.1-0.5 μmol/l) in MM cell lines and primary MM cells. CR2408 leads to fragmentation of cells and induces an accumulation in the subG1 phase accompanied with moderately decreased levels of cyclin D1 and cdk4 and strongly decreased levels of cdc25a, pRb and p53. Interruption of the cell cycle is reflected by inhibition of cell proliferation and is accompanied by decreased phosphorylation of 4E-BP1 and p70S6k. Treatment with CR2408 results in increased protein levels of Bim and pJNK and downregulation of Bad and Bcl-xL and activation of Caspases 3, 8 and 9. Furthermore, as HDAC inhibitors have shown synergism with other drugs, these effects were investigated and synergism was observed for combinations of CR2408 with doxorubicin and bortezomib. In conclusion, we have identified potent anti-myeloma activity for this novel HDAC inhibitor that gives further insights into the biological sequelae of HDAC inhibition in MM.
British Journal of Haematology 12/2011; 156(5):633-42. DOI:10.1111/j.1365-2141.2011.08983.x · 4.71 Impact Factor
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