Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigated the cytotoxicity of 5-azacytidine, a DNA methyltransferase inhibitor, against multiple myeloma (MM) cells, and characterized DNA damage-related mechanisms of cell death. 5-Azacytidine showed significant cytotoxicity against both conventional therapy-sensitive and therapy-resistant MM cell lines, as well as multidrug-resistant patient-derived MM cells, with IC(50) of approximately 0.8-3 micromol/L. Conversely, 5-azacytidine was not cytotoxic to peripheral blood mononuclear cells or patient-derived bone marrow stromal cells (BMSC) at these doses. Importantly, 5-azacytidine overcame the survival and growth advantages conferred by exogenous interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or by adherence of MM cells to BMSCs. 5-Azacytidine treatment induced DNA double-strand break (DSB) responses, as evidenced by H2AX, Chk2, and p53 phosphorylations, and apoptosis of MM cells. 5-Azacytidine-induced apoptosis was both caspase dependent and independent, with caspase 8 and caspase 9 cleavage; Mcl-1 cleavage; Bax, Puma, and Noxa up-regulation; as well as release of AIF and EndoG from the mitochondria. Finally, we show that 5-azacytidine-induced DNA DSB responses were mediated predominantly by ATR, and that doxorubicin, as well as bortezomib, synergistically enhanced 5-azacytidine-induced MM cell death. Taken together, these data provide the preclinical rationale for the clinical evaluation of 5-azacytidine, alone and in combination with doxorubicin and bortezomib, to improve patient outcome in MM.
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PMID:5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells. 1757 3

Homoharringtonine (HHT) is a plant alkaloid with antileukemic activity which is currently being used for treatment of acute and chronic leukemias. The present studies have evaluated the effect of HHT on proliferation and apoptosis in human myeloma cells. Myeloma cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptotic cells and cell cycle were evaluated by flow cytometry. Level of caspase-8, caspase-9, caspase-3, and DNA repair enzyme poly (ADP-ribose) polymerase (PARP), were investigated using Western blot analysis. We found that HHT significantly inhibited the proliferation of human multiple myeloma (MM) cell lines and tumor cells from patients with relapsed refractory MM in a dose-dependent manner. HHT also induced apoptosis in myeloma cells as evidenced by flow cytometric detection of annexin V binding assay. This apoptotic process was associated with the activation of caspase-8, caspase-9, caspase-3 and PARP. The results also demonstrate that HHT potentiates dexamethasone-induced killing of MM cells. These findings indicate that HHT may be effective in the treatment of MM.
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PMID:Homoharringtonine induces apoptosis and growth arrest in human myeloma cells. 1761 69

This study aims to evaluate and compare the antiproliferative and proapoptotic effects of resveratrol (trans-3,4',5-trihydoxystilbene) with two of its naturally occurring oligomers, epsilon-viniferin (a dimer) and miyabenol C (a trimer). Proliferation assays performed on myeloid and lymphoid cell lines show that the three compounds inhibit cell growth of all cell types tested, with miyabenol C being the most efficient (IC50 ranging from 10.8 to 29.4 muM). Further analysis performed on the multiple myeloma cell line U266 shows that all compounds modify cell cycle distribution probably via actions on different targets. Whereas cells treated with resveratrol accumulate in S phase, cells treated with epsilon-viniferin and miyabenol C accumulate in G2/M and G0/G1, respectively. Miyabenol C is also the most efficient at inducing cell death in U266 cells. All compounds induce apoptosis of U266 cells via mechanisms entirely dependent on caspase activation and associated with mitochondrial membrane potential disruption. Compounds do not act directly on the mitochondrial membrane, but could induce activation of upstream caspases such as caspase 8 and/or caspase 2, depending on the compound. In no case did upstream caspase 8 activation involve Fas/FasL interaction. Taken together, these results show that epsilon-viniferin and, more importantly, miyabenol C represent potent antitumor agents that require further investigation, either alone or in combination with resveratrol.
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PMID:Evaluation of antitumor effects of two vine stalk oligomers of resveratrol on a panel of lymphoid and myeloid cell lines: comparison with resveratrol. 1800 3

Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138(+) MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib-induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-kappaB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.
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PMID:Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. 1800 97

The resistance to arsenic trioxide (ATO) treatment is relatively common (55-80%) in multiple myeloma patients. This study found that ATO at clinically achievable concentrations (2-7 mumol/l) activated p38 mitogen-activated protein kinase (MAPK) in both myeloma cell lines and primary myeloma cells, a finding not previously well-documented in myeloma cells. Inhibition of p38 MAPK activation by pharmacological inhibitors (SB203580) or downregulation of p38 MAPK by siRNA significantly increased the apoptosis and/or growth inhibition induced by ATO treatment in myeloma cells. Combination of ATO and p38 MAPK inhibition abolished the interleukin-6 enhanced protection of myeloma cells against ATO treatment. The ATO-resistant cell line developed in our laboratory showed an increase in p38 MAPK activation. The increase of apoptosis by the combination of ATO and SB203580 was accompanied by the activation of caspase-9 and caspase-8 suggesting that both extrinsic and intrinsic apoptotic pathways are involved. Additionally, the p38 MAPK activation by ATO was associated with increased phosphorylation and upregulated expression of Heat shock protein 27. These results suggest that ATO-induced p38 MAPK activation plays an important role in the resistance to ATO in myeloma cells and that p38 MAPK inhibition may overcome resistance to ATO treatment in myeloma patients.
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PMID:P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells. 1817 54

Apo2 ligand (Apo2L)/TRAIL induces apoptosis of cancer cells that express the specific receptors while sparing normal cells. Because the tumor microenvironment protects myeloma from chemotherapy, we investigated whether hemopoietic stroma induces resistance to Apo2L/TRAIL apoptosis in this disease. Apo2L/TRAIL-induced death was diminished in myeloma cell lines (RPMI 8226, U266, and MM1s) directly adhered to a human immortalized HS5 stroma cell line but not adhered to fibronectin. In a Transwell assay, with myeloma in the upper well and HS5 cells in the lower well, Apo2L/TRAIL apoptosis was reduced when compared with cells exposed to medium in the lower well. Using HS5 and myeloma patients' stroma-conditioned medium, we determined that soluble factor(s) produced by stroma-myeloma interactions are responsible for a reversible Apo2/TRAIL apoptosis resistance. Soluble factor(s) attenuated procaspase-8, procaspase-3, and poly(ADP-ribose) polymerase cleavage and diminished mitochondrial membrane potential changes without affecting Bcl-2 family proteins and/or Apo2L/TRAIL receptors. Soluble factor(s) increased the baseline levels of the anti-apoptotic protein c-FLIP in all cell lines tested. Inhibition of c-FLIP by means of RNA interference increased Apo2/TRAIL sensitivity in RPMI 8226 cells. Unlike direct adhesion to fibronectin, soluble factor(s) have no impact on c-FLIP redistribution within cellular compartments. Cyclohexamide restored Apo2L/TRAIL sensitivity in association with down-regulation of c-FLIP, suggesting that c-FLIP synthesis, not intracellular traffic, is essential for soluble factor(s) to regulate c-FLIP. Additionally, IL-6 conferred resistance to Apo2L/TRAIL-mediated apoptosis in association with increased c-FLIP levels. In conclusion, the immune cytotoxic effect of Apo2L/TRAIL can be restored at least in part by c-FLIP pathway inhibitors.
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PMID:Bone marrow stroma confers resistance to Apo2 ligand/TRAIL in multiple myeloma in part by regulating c-FLIP. 1820 50

Since a variety of cell intrinsic and extrinsic molecular abnormalities cooperatively promote tumor formation in multiple myeloma (MM), therapeutic approaches that concomitantly target more than one molecule are increasingly attractive. We herein demonstrate the anti-myeloma effect of a cephalotaxus alkaloid, homoharringtonine (HHT), an inhibitor of protein synthesis, through the induction of apoptosis. HHT significantly reduced Mcl-1, a crucial protein involved in myeloma cell survival, in all three myeloma cell lines examined, whereas certain BH3-only proteins, such as Bim, Bik, and Puma, remained unchanged following HHT treatment, and their expression levels depended on the cell type. HHT also reduced the levels of c-FLIP(L/S), activated caspase-8, and induced active truncated-Bid. Thus, HHT-induced apoptosis appears to be mediated via both intrinsic and extrinsic apoptosis pathways, and the resultant imbalance between BH3-only proteins and Mcl-1 may be pivotal for apoptosis by HHT. In addition, HHT treatment resulted in reduced levels of beta-catenin and XIAP proteins, which also contribute to disease progression and resistance to chemotherapy in MM. In combination, HHT enhanced the effects of melphalan, bortezomib, and ABT-737. These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules.
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PMID:Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and beta-catenin. 1841 56

Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines and the viability of CD138(+) primary myeloma cells by induction of apoptosis, accompanied by an increase of acetylation of histones and activation of caspase-3, caspase-8, and caspase-9. Treatment with KD5170 caused a loss of mitochondrial membrane potential resulting in release of apoptogenic factors such as cytochrome c, Smac, and apoptosis-inducing factor. Furthermore, KD5170 induced oxidative stress and oxidative DNA damage in myeloma cells as evidenced by the up-regulation of heme oxygenase-1 and H2A.X phosphorylation. Combination of KD5170 with proteasome inhibitor bortezomib or tumor necrosis factor-related apoptosis-inducing ligand synergistically enhanced the antimyeloma activity. We further found that resistance of myeloma cells to KD5170 was associated with activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway under treatment with KD5170. Pretreatment with the mitogen-activated protein kinase inhibitor U0126 restored sensitivity to KD5170, suggesting that the combination of KD5170 with U0126 could overcome drug resistance. Growth of myeloma tumor xenografts in KD5170-treated nude mice was significantly inhibited and survival was prolonged. Histone acetylation was increased in spleen and tumor tissues of animals treated with KD5170. Our data indicate that KD5170 has potent antimyeloma activity in vitro and in vivo, which is mediated by DNA damage and mitochondrial signaling and subsequent induction of apoptosis.
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PMID:KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling. 1856 20

We demonstrate that blockade of the MEK/ERK signaling module, using the small-molecule inhibitors PD184352 or PD325901 (PD), strikingly enhances arsenic trioxide (ATO)-induced cytotoxicity in human myeloma cell lines (HMCLs) and in tumor cells from patients with multiple myeloma (MM) through a caspase-dependent mechanism. In HMCLs retaining a functional p53, PD treatment greatly enhances the ATO-induced p53 accumulation and p73, a p53 paralog, cooperates with p53 in caspase activation and apoptosis induction. In HMCLs carrying a nonfunctional p53, cotreatment with PD strikingly elevates the (DR4 + DR5)/(DcR1 + DcR2) tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors ratio and caspase-8 activation of ATO-treated cells. In MM cells, irrespective of p53 status, the combined PD/ATO treatment increases the level of the proapoptotic protein Bim (PD-mediated) and decreases antiapoptotic protein Mcl-1 (ATO-mediated). Moreover, Bim physically interacts with both DR4 and DR5 TRAIL receptors in PD/ATO-treated cells, and loss of Bim interferes with the activation of both extrinsic and intrinsic apoptotic pathways in response to PD/ATO. Finally, PD/ATO treatment induces tumor regression, prolongs survival, and is well tolerated in vivo in a human plasmacytoma xenograft model. These preclinical studies provide the framework for testing PD325901 and ATO combination therapy in clinical trials aimed to improve patient outcome in MM.
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PMID:Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways. 1858 68

The effects of the combination of simvastatin and lenalidomide were analyzed in myeloma. Myeloma cell lines and patient myeloma cells were incubated with different concentrations of lenalidomide, simvastatin, or the combination. Co exposure to simvastatin and lenalidomide resulted in a synergistic reduction of cell viability in myeloma cells. This effect was due to induction of apoptosis and inhibition of proliferation. The combination augmented induction of caspase-8 cleavage and enhanced down-regulation of pStat3. Mevalonate and GGOH abrogated the synergy between lenalidomide and simvastatin. These data provide a rationale for the clinical evaluation of lenalidomide and simvastatin in patients with myeloma.
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PMID:Inhibition of the mevalonate pathway potentiates the effects of lenalidomide in myeloma. 1862 17


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