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)

Dexamethasone (Dex), which is often used for the treatment of multiple myeloma, produces rapid reductions in tumor mass and improvement in disease symptoms; however, it is not curative, and drug-resistant cells eventually emerge. To elucidate this apparent paradox, we tested the effect of the bone marrow environment on myeloma cell response to this drug. To determine whether bone marrow stroma provides sufficient amounts of interleukin (IL)-6 to protect myeloma cells against the effects of Dex, we compared the production of IL-6 by marrow stromal cells from four myeloma patients before, during, and after exposure to 10(-7) M Dex, and found that even in the presence of this drug, stromal cells continued to produce IL-6, albeit in reduced concentrations. We tested the ability of stromal cells to protect myeloma cells, purified from the bone marrow of seven patients by cell sorting on the basis of CD38 and CD45 expression, and two light-scatter parameters, from Dex-induced apoptosis. In contrast to mature CD38+CD45- cells, which were not protected, coculture with stroma very effectively protected immature CD38+CD45+ myeloma cells from Dex. These data may explain the palliative efficacy of Dex treatment and provide a rationale for combining IL-6 antagonists with Dex to overcome the IL-6-mediated resistance of immature tumor cells.
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PMID:The bone marrow stromal environment is a major factor in myeloma cell resistance to dexamethasone. 965 34

We describe a 68-year-old patient presenting with recurrent fever, who eventually turned out to suffer from multiple myeloma. He was treated with Vincristine, Doxorubicin and Dexamethasone combination chemotherapy and intermediate dose Melphalan (70 mg/m2), respectively. Apart from periods of fever due to sepsis following chemotherapy, the recurrent fever disappeared after response, but recurred synchronously with progression of the disease. Recurrent fever in this case should be considered as a symptom of active multiple myeloma. This form of presentation of multiple myeloma has been described in literature only a few times.
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PMID:Fever as presenting symptom of multiple myeloma. 988 3

All-trans retinoic acid (ATRA) has been shown to inhibit in vitro growth of multiple myeloma (MM) cells, and this effect can be further potentiated by the addition of Dexamethasone (DEX). We here extended this study by testing the activity of 9-cis retinoic acid (9-cis RA) and 13-cis retinoic acid (13-cis RA), both alone and in combination with DEX, in two MM cell lines, U266 and RPMI 8226. Furthermore, we aimed at investigating the mechanisms involved in the interactions of retinoids and DEX in this setting. 9-cis RA appeared to be the most active agent in U266 cell line (IC50 = 1.2 mumol/l vs 10.5 and 9.8 mumol/l obtained with ATRA and 13-cis RA, respectively) while, in RPMI 8226 cell line, 9-cis RA and 13-cis RA were almost equally cytotoxic (IC50 = 1 and 0.8 mumol/l) and ATRA was less effective. Co-incubation with DEX resulted in a synergistic cytotoxic activity in both the cell lines except for the combinations DEX + 9-cis RA in U266 cell line and DEX + 13-cis RA in RPMI 8226 cell line, where the effect was merely additive. A synergistic cytotoxic effect of retinoids and DEX was also observed on fresh MM cells obtained from 7 patients. Both retinoids and DEX are known to be inducers of apoptosis; we verified that the combined inhibitory activity of retinoids and DEX could be attributed to an increased induction of apoptosis. This effect may be mediated by a reduced intracellular expression of BCL-2 protein, which indeed observed after prolonged in vitro treatment with retinoids. It has been described recently that an enhanced expression of BCL-2 protein can contribute to the occurrence of early chemoresistance; the downregulation of BCL-2 protein induced by retinoids could thus be exploited, by means of novel chemotherapy plus retinoids combinations, in order to improve the efficacy of conventional chemotherapy in MM.
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PMID:In vitro treatment with retinoids decreases bcl-2 protein expression and enhances dexamethasone-induced cytotoxicity and apoptosis in multiple myeloma cells. 1008 90

Previous studies demonstrate that interleukin-6 (IL-6) mediates growth and survival in human multiple myeloma (MM) cells via the MEK/MAPK and JAK/STAT signaling pathways, respectively. IL-6 also confers protection against Dexamethasone (Dex)-induced apoptosis via activation of protein tyrosine phosphatase (SHP2). In the current study, we characterized IL-6 triggered phophatidylinositol-3 kinase/Akt kinase (PI3-K/Akt) signaling in MM cells. IL-6 induces Akt/PKB phosphorylation in a time and dose dependent manner in MM.1S MM cells. IL-6 also induced phosphorylation of downstream targets of Akt, including Bad, GSK-3beta, and FKHR, confirming Akt activation. Inhibition of Akt activation by the PI3-K inhibitor LY294002 partially blocked IL-6 triggered MEK/MAPK activation and proliferation in MM.1S cells, suggesting cross-talk between PI3-K and MEK signaling. We demonstrate that Dex-induced apoptosis in MM.1S cells is mediated by downstream activation of caspase-9, with resultant caspase-3 cleavage; and conversely, that IL-6 triggers activation of PI3-K and its association with SHP2, inactivates caspase-9, and protects against Dex-induced apoptosis. LY294002 completely abrogates this signaling cascade, further confirming the importance of PI3-K/Akt signaling in conferring the protective effect of IL-6 against Dex-induced apoptosis. Finally, we show that IL-6 triggered PI3-K/Akt signaling in MM.1S cells inactivates forkhead transcriptional factor (FKHR), with related G1/S phase transition, whereas LY294002 blocks this signaling, resulting in upregulation of p27(KIP1) and G1 growth arrest. Our data therefore suggest that PI3-K/Akt signaling mediates growth, survival, and cell cycle regulatory effects of IL-6 in MM.
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PMID:Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. 1159 6

Treatment with thalidomide and dexamethasone was given to 26 patients with active, previously untreated multiple myeloma (MM). Thalidomide was administered in an initial dosage of 200 mg/d for 2 weeks and then increased as tolerated (in 200-mg increments at 2-week intervals) to a maximum daily dose of 800 mg. Dexamethasone was given orally in a dosage of 40 mg/d on days 1 through 4, 9 through 12, and 17 through 20 in odd cycles and 40 mg/d on days 1 through 4 in even cycles at monthly intervals. Response was defined as a decrease in serum and urine monoclonal (M)-protein by 50% or greater. Twenty (77%) of 26 patients with active MM exhibited a therapeutic response. Among the first seven patients treated with a thalidomide dose of 400 mg, grade III to IV skin toxicity developed in two. Drug titration was then stopped and the thalidomide dose maintained at 200 mg/d. Six (86%) of seven patients showed a response after thalidomide dose escalation, whereas 14 (74%) of 19 patients demonstrated a response with a constant thalidomide dose of 200 mg/d. Thalidomide alone produced a response in six (38%) of 16 patients with smoldering or indolent myeloma. The angiogenesis grade was elevated in only 8% of these patients. Thirty-two patients with relapsed myeloma were treated with thalidomide dosed at 200 mg/d, with 200-mg escalations every 2 weeks to a maximum daily dose of 800 mg. Prior chemotherapy had failed and five (16%) patients had experienced relapse following stem cell transplantation. Ten (38%) of the 26 patients who had received at least two cycles of therapy obtained a response.
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PMID:Therapeutic application of thalidomide in multiple myeloma. 1174 Aug 13

Our previous studies have characterized Dexamethasone (Dex)-induced apoptotic signaling pathways in multiple myeloma (MM) cells; however, related transcriptional events are not fully defined. In the present study, gene expression profiles of Dex-treated MM cells were determined using oligonucleotide arrays. Dex triggers early transient induction of many genes involved in cell defense/repair-machinery. This is followed by induction of genes known to mediate cell death and repression of growth/survival-related genes. The molecular and genetic alterations associated with Dex resistance in MM cells are also unknown. We compared the gene expression profiles of Dex-sensitive and Dex-resistant MM cells and identified a number of genes which may confer Dex-resistance. Finally, gene profiling of freshly isolated MM patient cells validates our in vitro MM cell line data, confirming an in vivo relevance of these studies. Collectively, these findings provide insights into the basic mechanisms of Dex activity against MM, as well as mechanisms of Dex-resistance in MM cells. These studies may therefore allow improved therapeutic uses of Dex, based upon targeting genes that regulate MM cell growth and survival.
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PMID:Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays. 1185 78

We have shown that thalidomide (Thal) and its immunomodulatory derivatives (IMiDs), proteasome inhibitor PS-341, and As(2)O(3) act directly on multiple myeloma (MM) cells and in the bone marrow (BM) milieu to overcome drug resistance. Although Thal/IMiDs, PS-341, and As(2)O(3) inhibit nuclear factor (NF)-kappaB activation, they also have multiple and varied other actions. In this study, we therefore specifically address the role of NF-kappaB blockade in mediating anti-MM activity. To characterize the effect of specific NF-kappaB blockade on MM cell growth and survival in vitro, we used an IkappaB kinase (IKK) inhibitor (PS-1145). Our studies demonstrate that PS-1145 and PS-341 block TNFalpha-induced NF-kappaB activation in a dose- and time-dependent fashion in MM cells through inhibition of IkappaBalpha phosphorylation and degradation of IkappaBalpha, respectively. Dexamethasone (Dex), which up-regulates IkappaBalpha protein, enhances blockade of NF-kappaB activation by PS-1145. Moreover, PS-1145 blocks the protective effect of IL-6 against Dex-induced apotosis. TNFalpha-induced intracellular adhesion molecule (ICAM)-1 expression on both RPMI8226 and MM.1S cells is also inhibited by PS-1145. Moreover, PS-1145 inhibits both IL-6 secretion from BMSCs triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs. However, in contrast to PS-341, PS-1145 only partially (20-50%) inhibits MM cell proliferation, suggesting that NF-kappaB blockade cannot account for all of the anti-MM activity of PS-341. Importantly, however, TNFalpha induces MM cell toxicity in the presence of PS-1145. These studies demonstrate that specific targeting of NF-kappaB can overcome the growth and survival advantage conferred both by tumor cell binding to BMSCs and cytokine secretion in the BM milieu. Furthermore, they provide the framework for clinical evaluation of novel MM therapies based upon targeting NF-kappaB.
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PMID:NF-kappa B as a therapeutic target in multiple myeloma. 1187 48

Oxaliplatin (L-OHP), a diaminocyclohexane platinum derivative, is an active and well tolerated anticancer drug which is presently used in the treatment of gastrointestinal tumours. Since the efficacy of L-OHP in the treatment of multiple myeloma (MM) has not yet been evaluated, we studied the antiproliferative activity of this compound in vitro in a panel of MM cell lines (XG1, XG1a, U266 and IM-9). We found that L-OHP inhibited the growth of MM cells at therapeutically achievable concentrations (IC(50): 5-10 microM after 24 h of exposure) and was more active than Cisplatin (CDDP) or Carboplatin (CBDCA). The activity of L-OHP was apparently not affected by interleukin-6 (IL-6), the major growth and survival factor of MM cells. We also found that L-OHP induced apoptotic cell death. We demonstrated that the combination of L-OHP with Dexamethasone (Dex) resulted in the enhancement of the anti-myeloma effects. L-OHP and Dex both induced poly adenosine diphosphate (ADP)-ribose polymerase (PARP) cleavage and this induction was enhanced by the combined treatment. L-OHP-induced apoptosis correlated with caspase-3 cleavage, but this correlation could not be demonstrated in Dex-treated cells. Taken together, these in vitro results provide a rationale for the experimental use of L-OHP in the treatment of MM patients and suggest therapeutic combinations of potential value.
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PMID:Oxaliplatin (L-OHP) treatment of human myeloma cells induces in vitro growth inhibition and apoptotic cell death. 1200 4

Cytokines of the gp130 family, particularly interleukin 6 (IL-6), play a central role in the growth and survival of malignant plasma cells. Recently, novel neurotrophin-1 (NNT-1)/B cell-stimulating factor-3 (BSF-3), also reported as cardiotrophin-like cytokine (CLC), was identified as a cytokine belonging to the gp130 family. BSF-3, similar to IL-6, exerts regulatory effects on normal B cell functions, but its functional significance in haematological malignancies has not been defined. The purpose of this study was to evaluate the biological effects and signalling pathways that are induced by BSF-3 in malignant plasma cells. Recombinant human BSF-3 was found to have growth stimulatory activity on plasmacytoma cell lines and primary tumour cells. In addition, BSF-3 was able to protect from Dexamethasone (Dex)-induced apoptosis. BSF-3 stimulated cell growth could not be inhibited by neutralizing anti-IL-6 or anti-IL-6 receptor antibodies, but was abrogated by anti-gp130 antibodies. In INA-6.Tu11 cells, a subline of the IL-6-dependent human plasma cell line INA-6 expressing gp130 and the receptor for leukaemia inhibitory factor (LIF), stimulation with BSF-3 induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). AG490, an inhibitor of Janus kinases, decreased BSF-3 induced cell growth in a dose-dependent manner. This correlated with a reduction of STAT3 phosphorylation levels, while p44/42 mitogen-activated protein kinase (MAPK) phosphorylation was not affected. In conclusion, BSF-3 is a novel myeloma growth and survival factor with a potential role in the pathophysiology of the disease.
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PMID:Functional significance of novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) for human myeloma cell growth and survival. 1463 78

In this study, we examined the effects of isoform-specific functional inhibitors of lysophosphatidic acid acyltransferase (LPAAT), which converts lysophosphatidic acid to phosphatidic acid, on multiple myeloma (MM) cell growth and survival. The LPAAT-beta inhibitors CT-32176, CT-32458, and CT-32615 induced >95% growth inhibition (P < 0.01) in MM.1S, U266, and RPMI8226 MM cell lines, as well as MM cells from patients (IC(50), 50-200 nM). We further characterized this LPAAT-beta inhibitory effect using CT-32615, the most potent inhibitor of MM cell growth. CT-32615 triggered apoptosis in MM cells via caspase-8, caspase-3, caspase-7, and poly (ADP-ribose) polymerase cleavage. Neither interleukin 6 nor insulin-like growth factor I inhibited CT-32615-induced apoptosis. Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-beta inhibitors. CT-32615-induced apoptosis was associated with phosphorylation of p53 and c-Jun NH(2)-terminal kinase (JNK); conversely, JNK inhibitor SP600125 and dominant-negative JNK inhibited CT-32615-induced apoptosis. Importantly, CT-32615 inhibited tumor necrosis factor-alpha-triggered nuclear factor-kappaB activation but did not affect either tumor necrosis factor-alpha-induced p38 mitogen-activated protein kinase phosphorylation or interleukin 6-triggered signal transducers and activators of transcription 3 phosphorylation. Finally, although binding of MM cells to bone marrow stromal cells augments MM cell growth and protects against dexamethasone-induced apoptosis, CT-32615 induced apoptosis even of adherent MM cells. Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM.
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PMID:Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. 1467 6


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