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)

Multiple myeloma (MM) is an as-yet incurable B-cell malignancy. Increased survival in vitro is a hallmark of MM cells, implying that a therapeutic potential may lie in circumventing antiapoptotic signals. We have previously reported that interferons (IFNs) sensitize MM cells to Fas/CD95-mediated apoptosis. In the present study, we explore the mechanism underlying this effect. In a wide screening of apoptosis-related genes, Apo2L/TRAIL (tumor necrosis factor [TNF]-related apoptosis inducing ligand) and Fas were identified as IFN targets. Sensitization to Fas-mediated apoptosis by IFNs was not affected by blocking Apo2L/TRAIL, suggesting that Apo2L/TRAIL is not a key mediator in this process. In contrast, we found that an elevated Fas expression was functionally linked to increased susceptibility to Fas-mediated apoptosis. This was further supported by the finding that IFN treatment enhanced Fas-mediated caspase-8 activation, one of the earliest signaling events downstream receptor activation. In addition, IFN treatment attenuated the interleukin 6 (IL-6)-dependent activation of signal transducer and activator of transcription 3 (Stat3), interfering with a known survival pathway in MM that has previously been linked with resistance to Fas-mediated apoptosis. Taken together, our results show that IFN-induced up-regulation of Fas sensitizes MM cells to Fas-mediated apoptosis and suggest that attenuation of Stat3 activation may be a potentially important event in this process.
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PMID:Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells. 1586 Jun 71

Survival and apoptosis are crucial aspects of the osteoclast life cycle. Although osteoclast survival has been extensively studied, little is known about the mechanisms involved in human osteoclast apoptosis. In the present study, cord blood monocytes (CBMs) were used as the source of human osteoclast precursors. When cultured in the presence of M-CSF and RANKL, CBMs formed multinucleated cells that expressed RANK and calcitonin receptor, and were able to resorb bone. These cells expressed TRAIL receptors (R1-R4). Surprisingly, although TRAIL-receptor expression was not detectable in osteoclasts from normal bone, osteoclasts from myeloma specimens did express TRAIL receptors to a variable extent. Significantly, we have shown for the first time that this pathway is indeed functional in human osteoclasts, and that apoptosis occurred and was significantly greater in the presence of TRAIL. In addition, we have shown that a Fas-activating antibody is also able to induce osteoclast apoptosis, as did TGFbeta, whereas the survival factor M-CSF decreased apoptosis. Overall, these findings suggest that death receptors, TRAIL receptors and Fas, could be involved in osteoclast apoptosis in humans.
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PMID:Death receptors, Fas and TRAIL receptors, are involved in human osteoclast apoptosis. 1593 19

In this study, we have evaluated the cytotoxic effect of combining two HDAC inhibitors, SAHA and TSA, with TRAIL in human multiple myeloma cell lines. Low doses of SAHA or TSA enhanced the cytotoxic and apoptotic effects of TRAIL and upregulated the surface expression of TRAIL death receptors (DR4 and/or DR5). SAHA and TSA induced G1 phase cell cycle growth arrest by upregulating p21(WAF1) and p27(Kip1) expression and by inhibiting E2F transcriptional activity. The enhanced TRAIL effect after pretreatment with HDAC inhibitors was consistent with the upregulation of the proapoptotic Bcl-2 family members (Bim, Bak, Bax, Noxa, and PUMA), the downregulation of the anti-apoptotic members of the Bcl-2 family (Bcl-2 and Bcl-X(L)), and IAPs. SAHA and TSA dissipated the mitochondrial membrane potential and enhanced the release of Omi/HtrA2 and AIF from the mitochondria to the cytosol. The cytotoxic effect of both SAHA and TSA was caspase- and calpain-independent. Inhibition of NF(kappa)B activation by the proteasome inhibitor, MG132, enhanced the apoptotic effect of TSA. Our study demonstrated the enhancing effects of HDAC inhibitors on apoptosis when combined with TRAIL and, for the first time, emphasized the role of AIF in mediating the cytotoxic effects of HDAC inhibitors.
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PMID:Interactive effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma. 1602 44

Interferon-alpha (IFN-alpha) is currently used for the therapy of multiple myeloma (MM) though it is only effective in some patients. IFN-alpha induces apoptosis in some MM cell lines and it has been proposed to occur through an autocrine loop involving Apo2L/TRAIL. We have analysed the sensitivity to IFN-alpha and Apo2L/TRAIL of five MM cell lines and found no correlation between the apoptosis inducing ability of both cytokines. IFN-alpha-induced apoptosis in MM cells was not prevented by a caspase-8 selective inhibitor (Z-IETD-fmk) or blocking Apo2L/TRAIL. However, human monocytes treated with IFN-alpha release bioactive Apo2L/TRAIL to culture media which was cytotoxic for MM cells resistant to IFN-alpha. We propose that Apo2L/TRAIL released from IFN-alpha-stimulated blood monocytes would be a major mediator of the anti-myeloma effect of IFN-alpha in vivo.
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PMID:Apo2L/TRAIL is an indirect mediator of apoptosis induced by interferon-alpha in human myeloma cells. 1624 31

A component of a traditional Thai condiment, 1'-acetoxychavicol acetate (ACA), is a natural compound, and it is obtained from rhizomes of the ethno-medicinal plant Languas galanga (Zingiberaceae). Our previous studies showed that ACA dramatically inhibited cellular growth of multiple myeloma cells in vivo and in vitro through the induction of apoptosis in association with the activation of caspase-8, inactivation of NF-kappaB, and down-regulation of anti-apoptotic proteins. Subsequently, we investigated the detailed apoptotic pathway of ACA and further demonstrated that ACA up-regulates the expression of both TNF-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) and TRAIL receptor death receptor 5 (DR5). In addition, TRAIL/R-Fc chimera neutralizes the ACA-induced apoptosis. These results suggest that the death signaling of TRAIL is involved in the ACA-induced apoptosis of myeloma cells, and provide a rationale for the induction of TRAIL/Apo2L by ACA, which could potentially be used as a novel therapeutic agent in patients with multiple myeloma.
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PMID:1'-Acetoxychavicol acetate induces apoptosis of myeloma cells via induction of TRAIL. 1628 31

In multiple myeloma (MM), neoplastic plasma cells accumulate in the bone marrow where their survival, proliferation, and apoptosis are controlled at multiple levels by interaction with the bone marrow microenvironment. Myeloma cells actively control these interactions by activating stromal and endothelial cells for production of survival factors, such as interleukin-6, and suppressing other cell types such as erythroblasts, normal B cell progenitors, and T-cells. In the present study, we identified primary osteoblasts as additional potential targets for myeloma cell-mediated suppression which was partly dependent on the death receptor ligand TRAIL. Besides killing of osteoblasts, myeloma cell lines sensitized osteoblasts to cell death mediated by recombinant TRAIL, whereas primary osteoblasts protected myeloma cells from TRAIL-mediated apoptosis that was mediated by osteoprotegerin (OPG). Besides increase of osteoclastogenesis and osteoclast activity, suppression of bone-forming cells by myeloma cells might contribute to bone loss in MM patients. In addition, clinical development of recombinant TRAIL as anti-myeloma therapy should include evaluation of potential side effects on viability of normal bone cells.
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PMID:A role of TRAIL in killing osteoblasts by myeloma cells. 1643 64

OPG (osteoprotegerin), a secreted member of the TNF (tumour necrosis factor) receptor superfamily, has a variety of biological functions which include the regulation of bone turnover. OPG is a potent inhibitor of osteoclastic bone resorption and has been investigated as a potential therapeutic for the treatment of both osteoporosis and tumour-induced bone disease. Indeed, in murine models of cancer-induced bone disease, inhibition of osteoclastic activity by OPG was also associated with a reduction in tumour burden. The discovery that OPG can bind to and inhibit the activity of TRAIL (TNF-related apoptosis-inducing ligand) triggered extensive research into the potential role of OPG in the regulation of tumour cell survival. A number of reports from studies using in vitro models have shown that OPG protects tumour cells from the effects of TRAIL, thereby possibly providing tumour cells that produce OPG with a survival advantage. However, the ability of OPG to act as a tumour cell survival factor remains to be verified using appropriate in vivo systems. A third area of interest has been the use of OPG as a prognostic marker in various cancer types, including myeloma, breast and prostate cancer. This review provides an overview of the role of OPG in cancer, both in cancer-induced bone disease and in tumour growth and survival.
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PMID:Role of osteoprotegerin (OPG) in cancer. 1646 70

We evaluated the ability of 2 human mAbs directed against TRAILR1 (HGS-ETR1) and TRAILR2 (HGS-ETR2) to kill human myeloma cells. HGS-ETR1 and HGS-ETR2 mAbs killed 15 and 9 human myeloma cell lines (HMCLs; n = 22), respectively. IL-6, the major survival and growth factor for these HMCLs, did not prevent their killing. Killing induced by either HGS-ETR1 or HGS-ETR2 was correlated with the cleavage of Mcl-1L, a major molecule for myeloma survival. Mcl-1L cleavage and anti-TRAILR HMCL killing were dependent on caspase activation. Kinetic studies showed that Mcl-1L cleavage occurred very early (less than 1 hour) and became drastic once caspase 3 was activated. Our data showed that both the extrinsic (caspase 8, Bid) and the intrinsic (caspase 9) pathways are activated by anti-TRAIL mAb. Finally, we showed that the HGS-ETR1 and, to a lesser extent, the HGS-ETR2 mAbs were able to induce the killing of primary myeloma cells. Of note, HGS-ETR1 mAb was able to induce the death of medullary and extramedullary myeloma cells collected from patients at relapse. Taken together, our data clearly encourage clinical trials of anti-TRAILR1 mAb in multiple myeloma, especially for patients whose disease is in relapse, at the time of drug resistance.
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PMID:Mcl-1L cleavage is involved in TRAIL-R1- and TRAIL-R2-mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAbs in myeloma cells. 1663 30

Multiple myeloma (MM) is often associated with an increased osteoclast (OC) activity. Using an in vitro osteoclastogenesis model consisting of MM unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs), we showed that T cells support OC formation and survival. Differently, in T cell-depleted MM PBMC cultures, exogenous macrophage-colony stimulating factor (M-CSF) and receptor activated of nuclear factor-kappaB ligand (RANKL) were necessary for osteoclastogenesis. We found RANKL, OPG, and TRAIL overexpression by fresh MM T cells. Despite high osteoprotegerin (OPG) levels, the persistence of osteoclastogenesis can be related to the formation of the OPG/TRAIL complex. Our results highlight that MM T cells support OC formation and survival, possibly involving OPG/TRAIL interaction.
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PMID:The role of OPG/TRAIL complex in multiple myeloma: the OPG/TRAIL complex in an in vitro osteoclastogenesis model derived from human multiple myeloma-bone disease. 1683 34

Multiple myeloma (MM) is an incurable B-cell malignancy, requiring new therapeutic strategies. We have found that synthetic alkyl-lysophospholipids (ALPs) edelfosine and perifosine induced apoptosis in MM cell lines and patient MM cells, whereas normal B and T lymphocytes were spared. ALPs induced recruitment of Fas/CD95 death receptor, Fas-associated death domain-containing protein, and procaspase-8 into lipid rafts, leading to the formation of the death-inducing signaling complex (DISC) and apoptosis. TNF-related apoptosis-inducing ligand receptor-1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5, as well as Bid, were also recruited into lipid rafts, linking death receptor and mitochondrial signaling pathways. ALPs induced mitochondrial cytochrome c release. Bcl-X(L) overexpression prevented cytochrome c release and apoptosis. A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine. Fas/CD95 retrovirus transduction bestowed edelfosine sensitivity in these cells. A Fas/CD95 mutant lacking part of the intracellular domain was ineffective. Lipid raft disruption prevented ALP-induced Fas/CD95 clustering, DISC formation, and apoptosis. ALP-induced apoptosis was Fas/CD95 ligand (FasL/CD95L) independent. ALP-induced recruitment of death receptors in lipid rafts potentiated MM cell killing by FasL/CD95L and TRAIL. These data uncover a novel lipid raft-mediated therapy in MM involving concentration of death receptors in membrane rafts, with Fas/CD95 playing a major role in ALP-mediated apoptosis.
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PMID:Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. 1700 75


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