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)

Overexpression of Bcl-2 in myeloma cells results in resistance to drugs such as dexamethasone (DEX), adenovirus-mediated delivery of p53 (Ad-p53), and paclitaxel (TAX), which work through the intrinsic apoptotic pathway. Bcl-2 antisense oligodeoxynucleotides (Bcl-2-ASO) have been shown to induce apoptosis in cancer cells, as a single agent or, better, in combination with chemotherapy. We hypothesized that down-regulation of Bcl-2 by Bcl-2-ASO will sensitize drug-resistant myeloma cells to undergo apoptosis. In this paper we report a detailed time/dose study of the effect of Bcl-2-ASO on myeloma cells with varying levels of Bcl-2. Treatment of myeloma cells expressing relatively low levels of Bcl-2 with Bcl-2-ASO resulted in a substantial apoptosis concomitant with a substantial depletion of Bcl-2 protein. Maximal apoptosis was observed at 5 to 10 microg/mL Bcl-2-ASO, following 4 days of treatment. Down-regulation of Bcl-2 and apoptosis were time and dose dependent and were sequence specific. In these cell lines, apoptosis was accompanied by activation of caspase-9 and caspase-3 and by release of cytochrome c to the cytosol. In contrast, high Bcl-2-expressing myeloma cells were practically resistant to Bcl-2-ASO. Most important, however, pretreatment of myeloma cells expressing high levels of Bcl-2 with Bcl-2-ASO increased the extent of DEX-, TAX-, and Ad-p53-induced apoptosis from 10%-20% to 70%-90%. Increased apoptosis was accompanied by additional decrease in Bcl-2 protein. Similar results for down-regulation of Bcl-2 and apoptosis were obtained with freshly isolated myeloma cells. These data support development of clinical trials with combinations of Bcl-2-ASO and DEX, TAX, or Ad-p53 in the treatment of refractory myeloma patients.
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PMID:Potentiation of dexamethasone-, paclitaxel-, and Ad-p53-induced apoptosis by Bcl-2 antisense oligodeoxynucleotides in drug-resistant multiple myeloma cells. 1252 96

Mitochondria play central roles in cellular metabolism and apoptosis and are a major source of reactive oxygen species (ROS). We investigated the role of ROS and mitochondria in radiation-induced apoptosis in multiple myeloma cells. Two distinct levels of ROS were generated following irradiation: a small increase observed early, and a pronounced late increase, associated with depletion of reduced glutathione (GSH) and collapse of mitochondrial membrane potential (deltapsi(m)). Exogenous ROS and caspase-3 induced deltapsi(m) drop and cytochrome c release from mitochondria, which could be prevented by molecular (dominant-negative caspase-9) and pharmacologic (zVAD-fmk) caspase inhibitors and overexpression of Bcl-2. Exogenous ROS also induced mitochondrial permeability transition (PT) pore opening and cytochrome c release in isolated mitochondria, which could be blocked by inhibition of PT with cyclosporin A. These results indicate that the late ROS production is associated with increased PT pore opening and decreased deltapsi(m), and GSH, events associated with caspase activation and cytochrome c release.
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PMID:The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. 1270 Jun 32

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we investigated the antiproliferative effect of monensin on human myeloma cell lines. Monensin significantly inhibited the proliferation of myeloma cell lines examined with IC50 of about 1 micro M. Cell cycle analysis indicated that monensin induced a G1 and/or a G2-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of this drug on cell cycle-related proteins in NCI-H929 cells. Monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A, cyclin B1, cyclin D1 and cyclin E proteins but did not alter CDK4 protein. While p21 was increased by monensin, p27 was not. In addition, monensin markedly enhanced the binding of p21 with CDK6 and cdc2. Furthermore, the activities of CDK2- and CDK6-associated kinases were reduced in association with hypophosphorylation of Rb protein. The activity of cdc2-associated kinase was decreased, which was accompanied by reduction of cdc25C phosphatase. Also, monensin induced apoptosis in myeloma cells, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. This apoptotic process was associated with down-regulation of Bcl-2, loss of mitochondria transmembrane potential (Deltapsim) and an increase of caspase-3 activity. In addition, monensin caused the up-regulation of ERK and p38 kinase activities. Taken together, these results have demonstrated for the first time that monensin potently inhibited the proliferation of human myeloma cell lines, especially NCI-H929 cells, via cell cycle arrest in association with p21 and apoptosis.
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PMID:Monensin-mediated growth inhibition in NCI-H929 myeloma cells via cell cycle arrest and apoptosis. 1279 94

HMG-CoA reductase is the rate-limiting enzyme of the mevalonate pathway leading to the formation of cholesterol and isoprenoids such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP). The inhibition of HMG-CoA reductase by lovastatin induced apoptosis in plasma cell lines and tumor cells from patients with multiple myeloma. Here we show that cotreatment with mevalonate or geranylgeranyl moieties, but not farnesyl groups, rescued myeloma cells from lovastatin-induced apoptosis. In addition, the inhibition of geranylgeranylation by specific inhibition of geranylgeranyl transferase I (GGTase I) induced the apoptosis of myeloma cells. Apoptosis triggered by the inhibition of geranylgeranylation was associated with reduction of Mcl-1 protein expression, collapse of the mitochondrial transmembrane potential, expression of the mitochondrial membrane protein 7A6, cytochrome c release from mitochondria into the cytosol, and stimulation of caspase-3 activity. These results imply that protein geranylgeranylation is critical for regulating myeloma tumor cell survival, possibly through regulating Mcl-1 expression. Our results show that pharmacologic agents such as lovastatin or GGTase inhibitors may be useful in the treatment of multiple myeloma.
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PMID:Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels. 1285 56

Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.
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PMID:Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance. 1285 65

The antiapoptotic protein bcl-x(L) is upregulated in a variety of solid tumors and in primary hematologic malignancies such as multiple myeloma. Activated caspase-3 cleaves proteins essential for cell survival, including bcl-x(L). To explore the potential of caspase-3 as a cytotoxic and immunostimulatory molecule in the treatment of malignancy, an RU486-inducible caspase-3 retrovirus was constructed, validated, and used to transduce first 3T3 and subsequently murine myeloma B9BM1 cells (creating the cell line B9BM-C3). After induction, apoptotic cell death of 3T3 and B9BM-C3 cells began by 4 h and was complete by 48 h postinduction, while nontransduced cells remained viable. Annexin V staining demonstrated 43, 76, and 98% apoptotic cell death at 12, 18, and 24 h postinduction. Activation of caspase-3 was evident in induced cells and cell death could be inhibited by the addition of a caspase-3-specific inhibitor. Overexpression of the myeloma-associated oncogene FGFR3, which upregulates bcl-x(L), delayed but did not prevent caspase-3-mediated killing. B9BM-C3 cells formed tumors after subcutaneous injection in mice. Early treatment with RU486 eradicated tumors; however, rechallenge of treated mice failed to demonstrate evidence of immunoprotection. These results indicate that therapeutic attempts to induce caspase-3 in malignant cells may prove useful in the treatment of bcl-x(L)-expressing tumors.
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PMID:RU486-inducible retrovirus-mediated caspase-3 overexpression is cytotoxic to bcl-xL-expressing myeloma cells in vitro and in vivo. 1290 45

Ginseng (the root of Panax ginseng C.A. Meyer, Araliaceae) has been used as a crude drug taken orally for preventive and therapeutic purposes in Asian countries as a traditional medicine. In the current study, we have investigated the antitumor effect of a novel ginseng protopanaxadiol saponin bacterial metabolic derivative, 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (IH-901), in eight human myeloma cell lines. IH-901 inhibited the proliferation of all myeloma cell lines examined. Despite the fibroblast growth factor receptor 3 (FGFR3) overexpression due to a chromosomal translocation t(4;14)(q16.3;q32.3) in KMS-11 myeloma cells, IH-901 induced apoptosis in a dose- and time-dependent way in this cell line. Treatment of KMS-11 with IH-901 resulted in the formation of internucleosomal DNA fragments, poly (ADP-ribose) polymerase cleavage, and the activation of caspase-3. IH-901 also caused the down-regulation of FGFR3 mRNA and protein expression and inhibited ERK activity in KMS-11 cells. Our results demonstrate that IH-901 induces apoptosis and inhibits FGFR3 expression and signaling in KMS-11 cells, suggesting candidacy for the chemoprevention and the treatment of myeloma.
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PMID:A novel ginseng saponin metabolite induces apoptosis and down-regulates fibroblast growth factor receptor 3 in myeloma cells. 1296 89

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

Erythropoiesis is a complex multistep process encompassing the differentiation of hemopoietic stem cells to mature erythrocytes. The steps involved in this complex differentiation process are numerous and involve first the differentiation to early erythoid progenitors (burst-forming units-erythroid, BFU-E), then to late erythroid progenitors (colony-forming units-erythroid) and finally to morphologically recognizable erythroid precursors. A key event of late stages of erythropoiesis is nuclear condensation, followed by extrusion of the nucleus to produce enucleated reticulocytes and finally mature erythrocytes. During the differentiation process, the cells became progressively sensitive to erythropoietin that controls both the survival and proliferation of erythroid cells. A normal homeostasis of the erythropoietic system requires an appropriate balance between the rate of erythroid cell production and red blood cell destruction. Growing evidences outlined in the present review indicate that apoptotic mechanism play a relevant role in the control of erythropoiesis under physiologic and pathologic conditions. Withdrawal of erythropoietin or stimulation of death receptors such as Fas or TRAIL-Rs leads to activation of a subset of caspase-3, -7 and -8, which then cleave the transcription factors GATA-1 and TAL-1 and trigger apoptosis. In addition, there is evidence that a number of caspases are physiologically activated during erythroid differentiation and are functionally required for erythroid maturation. Several caspase substrates are cleaved in differentiating cells, including the protein acinus whose activation by cleavage is required for chromatin condensation. The studies on normal erythropoiesis have clearly indicated that immature erythroid precursors are sensitive to apoptotic triggering mediated by activation of the intrinsic and extrinsic apoptotic pathways. These apoptotic mechanisms are frequently exacerbated in some pathologic conditions, associated with the development of anemia (ie, thalassemias, multiple myeloma, myelodysplasia, aplastic anemia). The considerable progress in our understanding of the apoptotic mechanisms underlying normal and pathologic erythropoiesis may offer the way to improve the treatment of several pathologic conditions associated with the development of anemia.
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PMID:Apoptotic mechanisms in the control of erythropoiesis. 1520 42

The anti-angiogenic properties of thalidomide have led to the use of the agent as a remedy for multiple myeloma. Nevertheless, the anti-angiogenic moiety of thalidomide remains unidentified. In this study we examined the anti-angiogenic effects of thalidomide in an in vitro model using a three-dimensional collagen gel culture. Angiogenesis was significantly inhibited when the culture was treated with thalidomide plus cytochrome P-450 (CYP2B4), and the migrating cells and tubules were positive for active-caspase-3 in an accompanying immunohistochemical investigation. Transmission electron microscopic observation also confirmed that active-caspase-3-positive cells demonstrated apoptotic characteristics. This study is the first to morphologically demonstrate the effect of thalidomide in directly inducing the apoptosis of new tubules and migrating cells on a three-dimensional collagen gel culture of aorta. Taken together with earlier findings, our new results indicate that the thalidomide-induced inhibition of angiogenesis involves apoptosis in addition to the suppression of TNF-alpha and inhibition of cell migration from aorta explants, i.e., the factors important for capillarogenesis.
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PMID:Anti-angiogenic effects of thalidomide: expression of apoptosis-inducible active-caspase-3 in a three-dimensional collagen gel culture of aorta. 1522 9


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