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

The Fas/APO-1/CD95 ligand (CD95L) and the recently cloned TRAIL ligand belong to the TNF-family and share the ability to induce apoptosis in sensitive target cells. Little information is available on the degree of functional redundancy between these two ligands in terms of target selectivity and intracellular signalling pathway(s). To address these issues, we have expressed and characterized recombinant mouse TRAIL. Specific detection with newly developed rabbit anti-TRAIL antibodies showed that the functional TRAIL molecule released into the supernatant of recombinant baculovirus-infected Sf9 cells is very similar to that associated with the membrane fraction of Sf9 cells. CD95L resistant myeloma cells were found to be sensitive to TRAIL, displaying apoptotic features similar to those of the CD95L- and TRAIL-sensitive T leukemia cells Jurkat. To assess if IL-1beta-converting enzyme (ICE) and/or ICE-related proteases (IRPs) (caspases) are involved in TRAIL-induced apoptosis of both cell types, peptide inhibition experiments were performed. The irreversible IRP/caspase-inhibitor Ac-YVAD-cmk and the reversible IRP/caspase-inhibitor Ac-DEVD-CHO blocked the morphological changes, disorganization of plasma membrane phospholipids, DNA fragmentation, and loss of cell viability associated with TRAIL-induced apoptosis. In addition, cells undergoing TRAIL-mediated apoptosis displayed cleavage of poly(ADP)-ribose polymerase (PARP) that was completely blocked by Ac-DEVD-CHO. These results indicate that TRAIL seems to complement the activity of the CD95 system as it allows cells, otherwise resistant, to undergo apoptosis triggered by specific extracellular ligands. Conversely, however, induction of apoptosis in sensitive cells by TRAIL involves IRPs/caspases in a fashion similar to CD95L. Thus, differential sensitivity to CD95L and TRAIL seems to map to the proximal signaling events associated with receptor triggering.
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PMID:Interleukin 1 beta-converting enzyme related proteases/caspases are involved in TRAIL-induced apoptosis of myeloma and leukemia cells. 910 50

TRAIL, the ligand for the newly discovered DR-4 and DR-5 receptor, is a member of the TNF family of death signal transduction proteins with a mechanism of cell death similar to that of Fas and Fas ligand (Fas-L) system. We provide first time evidence that TRAIL is a potent inducer of apoptosis in multiple myeloma (MM) cell lines. TRAIL effectively induced extensive apoptosis in 8226 and ARP-1 MM cells in a time- and dose-dependent manner. Apoptosis with TRAIL reached about 80% within 48 h of treatment with a dose of 160 ng/ml. Furthermore, we provide first time evidence that similar to Fas, TRAIL-induced apoptosis is not blocked by bcl-2 in MM cell lines. Most importantly, TRAIL induced substantial apoptosis in freshly isolated, flow-sorted myeloma cells obtained from different MM patients expressing variable levels of bcl-2. Finally, we demonstrate for the first time that TRAIL is not cytotoxic to purified CD34+/CD45dim hematopoietic stem cells and does not inhibit CFU-GM or BFU-E colony formation in methylcellulose.
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PMID:TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells. 1055 57

TRAIL, the ligand for the newly discovered DR-4 and DR-5 receptor is a member of the tumour necrosis factor (TNF) family of death signal tranduction proteins with a mechanism of cell death, similar to the Fas and Fas ligand (Fas-L) system. Here, we provide first time evidence that TRAIL and TNF-alpha are potent inducers of apoptosis in multiple myeloma (MM) cell lines and freshly isolated myeloma cells. TRAIL effectively induced extensive apoptosis in 8226 and ARP-1 MM cells in a time- and dose-dependent manner reaching 80% within 48 h of treatment with a dose of 160 ng/ml. Bcl-2 transfected 8226 and ARP-1 cells were equally sensitive to apoptosis by TRAIL. Apoptosis with TNFalpha, reached >60% within 48 h of treatment with a dose of 160 ng/ml. In addition to MM cell lines, freshly isolated, flow-sorted myeloma cells from 8 different MM patients expressing variable levels of bcl-2 were equally sensitive to both TRAIL and TNF-alpha. We have previously shown that anti-Fas-induced apoptosis is not blocked by endogenous or ectopic bcl-2 in MM cell lines. Here we extend our observation with Fas to include TNF-alpha and TRAIL to the apoptotic signals that are not be blocked by bcl-2, in MM cells.
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PMID:Apoptosis-induced by TRAIL AND TNF-alpha in human multiple myeloma cells is not blocked by BCL-2. 1062 26

The anti-CD20 chimeric monoclonal antibody rituximab (Rituxan) is used to treat patients with various B-cell tumors, including patients with plasma cell dyscrasias who have CD20+ disease. Many patients with CD20+ disease have either primary unresponsive disease or progress after initially responding to rituximab; therefore, understanding how tumor cells are, or become, resistant to rituximab is of clinical relevance. In this report, we determined whether tumor cells express antigens that block complement-mediated lysis or antibody-dependent cell-mediated cytotoxicity (ADCC) and thereby contribute to rituximab resistance. We demonstrate that expression of the complement regulator CD59 is associated with resistance to rituximab-mediated complement lysis of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Moreover, neutralization of CD59 using a blocking monoclonal antibody reversed resistance to rituximab-mediated complement lysis of CD20++ CD59++ ARH-77 MM cells. In addition, we demonstrate the presence of CD59 and rituximab binding on viable tumor cells from patients with MM and Waldenstrom's macroglobulinemia with progressive disease despite rituximab therapy. Last, we also examined MM and NHL B-cell lines, as well as patient tumor cells, for the expression of other antigens that may have a role in blocking ADCC activity, such as Fas ligand (FasL), MUCI, or TRAIL. FasL, MUC1, and/or TRAIL were coexpressed with complement regulators on many of these cells. These studies therefore show that complement regulators, particularly CD59 and antigens that may block ADCC, are present on various B-cell tumors and associated with rituximab resistance in patients. A prospective, clinical study is assessing the role of these antigens in mediating rituximab resistance.
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PMID:Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies. 1139 5

SUMMARY: The anti-CD20 chimeric monoclonal antibody rituximab (Rituxan) is used to treat patients with various B-cell tumors, including patients with plasma cell dyscrasias who have CD20+ disease. Many patients with CD20+ disease have either primary unresponsive disease or progress after initially responding to rituximab; therefore, understanding how tumor cells are, or become, resistant to rituximab is of clinical relevance. In this report, we determined whether tumor cells express antigens that block complement-mediated lysis or antibody-dependent cell-mediated cytotoxicity (ADCC) and thereby contribute to rituximab resistance. We demonstrate that expression of the complement regulator CD59 is associated with resistance to rituximab-mediated complement lysis of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Moreover, neutralization of CD59 using a blocking monoclonal antibody reversed resistance to rituximab-mediated complement lysis of CD20++ CD59++ ARH-77 MM cells. In addition, we demonstrate the presence of CD59 and rituximab binding on viable tumor cells from patients with MM and Waldenstrom's macroglobulinemia with progressive disease despite rituximab therapy. Last, we also examined MM and NHL B-cell lines, as well as patient tumor cells, for the expression of other antigens that may have a role in blocking ADCC activity, such as Fas ligand (FasL), MUC1, or TRAIL. FasL, MUC1, and/or TRAIL were coexpressed with complement regulators on many of these cells. These studies therefore show that complement regulators, particularly CD59 and antigens that may block ADCC, are present on various B-cell tumors and associated with rituximab resistance in patients. A prospective, clinical study is assessing the role of these antigens in mediating rituximab resistance.
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PMID:Tumor Cell Expression of CD59 Is Associated With Resistance to CD20 Serotherapy in Patients With B-Cell Malignancies. 1139 43

Multiple myeloma (MM) remains incurable and novel treatments are urgently needed. Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) in MM. TRAIL/Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines, including cells sensitive or resistant to dexamethasone (Dex), doxorubicin (Dox), melphalan, and mitoxantrone. TRAIL/Apo2L also overcame the survival effect of interleukin 6 on MM cells and did not affect the survival of peripheral blood and bone marrow mononuclear cells and purified B cells from healthy donors. The status of the TRAIL receptors (assessed by immunoblotting and flow cytometry) could not predict TRAIL sensitivity of MM cells. The anti-MM activity of TRAIL/Apo2L was confirmed in nu/xid/bg mice xenografted with human MM cells; TRAIL (500 microg intraperitoneally daily for 14 days) was well tolerated and significantly suppressed the growth of plasmacytomas. Dox up-regulated the expression of the TRAIL receptor death receptor 5 (DR5) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to, but also against those resistant to, Dex- or Dox-induced apoptosis. Nuclear factor (NF)-kappaB inhibitors, such as SN50 (a cell-permeable inhibitor of the nuclear translocation and transcriptional activity of NF-kappaB) or the proteasome inhibitor PS-341, enhanced the proapoptotic activity of TRAIL/Apo2L against TRAIL-sensitive MM cells, whereas SN50 reversed the TRAIL resistance of ARH-77 and IM-9 MM cells. Importantly, normal B lymphocytes were not sensitized to TRAIL by either Dox, SN50, or PS-341. These preclinical studies suggest that TRAIL/Apo2L can overcome conventional drug resistance and provide the basis for clinical trials of TRAIL-based treatment regimens to improve outcome in patients with MM. (Blood. 2001;98:795-804)
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PMID:TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. 1146 81

It has been reported that interferons (IFNs) may have antitumor activity in multiple myeloma (MM). The mechanism for their effect on MM, however, remains elusive. This study shows that IFN-alpha and -beta, but not -gamma, induce apoptosis characterized by Annexin V positivity, nuclear fragmentation and condensation, and loss of clonogenicity in 3 MM cell lines (U266, RPMI-8266, and NCI-H929), and in plasma cells from 10 patients with MM. Apo2 ligand (Apo2L, also TRAIL) induction was one of the earliest events following IFN administration in U266 cells. Treatment of these cells with TRAIL, but not with Fas agonistic antibodies, induces apoptosis. Cell death induced by IFNs and Apo2L in U266 cells was partially blocked by a dominant-negative Apo2L receptor, DR5, demonstrating the functional significance of Apo2L induction. This study shows that IFNs activate caspases and the mitochondrial-dependent apoptotic pathway, possibly mediated by Apo2L production. Thus, IFN-alpha and -beta induce cytochrome c release from mitochondria starting at 12 hours, with an amplified release seen at 48 hours. Moreover, Bid cleavage precedes the initial cytochrome c release, whereas the late, amplified cytochrome c release coincides with changes in levels of Bcl-2, Bcl-X(L), and reduction of mitochondrial membrane potential. These results link the Apo2L induction and modulation of Bcl-2 family proteins to mitochondrial dysfunction. Furthermore, IFNs and Apo2L induce cell death of CD38(+)/CD45(-/dim) plasma cells, without significant effect on nonplasma blood cells, in a caspase and Bcl-2 cleavage-dependent manner. These results warrant further clinical studies with IFNs and Apo2L in MM.
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PMID:Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced apoptosis in multiple myeloma. 1156 6

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced both cytotoxic (apoptosis) and cytostatic (cell cycle perturbation) effects on the human myeloid K562 cell line. TRAIL stimulated caspase 3 and nitric oxide synthase (NOS) activities, and both pathways cooperate in mediating inhibition of K562 survival/growth. This was demonstrated by the ability of z-VAD-fmk, a broad inhibitor of effector caspases, and N-nitro-L-arginine methyl ester (L-NAME), an NOS pharmacologic inhibitor, to completely (z-VAD-fmk) or partially (L-NAME) suppress the TRAIL-mediated inhibitory activity. Moreover, z-VAD-fmk was able to block TRAIL-mediated apoptosis and cell cycle abnormalities and increase of NOS activity. The addition of the NO donor sodium nitroprusside (SNP) to K562 cells reproduced the cytostatic effect of TRAIL without inducing apoptosis. When TRAIL was associated to SNP, a synergistic increase of apoptosis and inhibition of clonogenic activity was observed in K562 cells as well as in other myeloblastic (HEL, HL-60), lymphoblastic (Jurkat, SupT1), and multiple myeloma (RPMI 8226) cell lines. Although SNP greatly augmented TRAIL-mediated antileukemic activity also on primary leukemic blasts, normal erythroid and granulocytic cells were less sensitive to the cytotoxicity mediated by TRAIL with or without SNP. These data indicate that TRAIL promotes cytotoxicity in leukemic cells by activating effector caspases, which directly lead to apoptosis and stimulate NO production, which mediates cell cycle abnormalities. Both mechanisms seem to be essential for TRAIL-mediated cytotoxicity.
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PMID:Activation of the nitric oxide synthase pathway represents a key component of tumor necrosis factor-related apoptosis-inducing ligand-mediated cytotoxicity on hematologic malignancies. 1156 10

TNF-related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L) is a member of the TNF superfamily of death ligands that selectively induces apoptosis in tumour cells of diverse origins. In this report, we have reviewed recent studies examining TRAIL/Apo2L-induced apoptosis in multiple myeloma (MM), a B-cell malignancy which, in spite of its initial sensitivity to steroids, cytotoxic and high-dose chemotherapy, remains incurable. Recently, we demonstrated that TRAIL/Apo2L induces apoptosis of steroid- and chemotherapy-sensitive and resistant MM cell lines. Moreover, TRAIL/Apo2L selectively induced apoptosis of patient MM tumour cells while sparing non-malignant bone marrow and peripheral blood mononuclear cells. In addition, TRAIL/Apo2L inhibited the growth of human plasmacytomas xenografted into mice. Importantly, TRAIL/Apo2L-induced apoptosis was unaffected by IL-6, a potent growth and survival factor for MM cells which, as we and others have previously shown, blocks various pro-apoptotic signals including Fas ligand, which like TRAIL/Apo2L is also a member of the TNF family of ligands. In view of the potential clinical application of TRAIL/Apo2L to the treatment of MM, we have attempted to discern intracellular mechanisms of action and resistance for TRAIL/Apo2L in MM, along with strategies to increase sensitivity and overcome resistance of MM cells to TRAIL/Apo2L. These studies demonstrated that doxorubicin, an agent which is commonly used to treat MM patients, upregulated the expression of the DR5 death-signalling TRAIL receptor and synergistically enhanced the pro-apoptotic effect of TRAIL on MM cells. Moreover, NF-kappaB inhibitors such as SN50 (a cell permeable inhibitor of NF-kappaB nuclear translocation) as well as the proteasome inhibitor PS-341, which is currently in Phase II clinical trials, also enhanced the pro-apoptotic activity of TRAIL/Apo2L in MM cells. Lastly, TRAIL/Apo2L-induced apoptosis in MM cells was dependent on caspase-8 activation and inhibited by the caspase regulatory proteins FLIP and cIAP2. These studies provide a framework for the use of TRAIL/Apo2L as a single agent or as part of combination therapy for the treatment of MM.
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PMID:Concepts in the use of TRAIL/Apo2L: an emerging biotherapy for myeloma and other neoplasias. 1177 67

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2 ligand) effectively kills multiple myeloma (MM) cells in vitro irrespective of refractoriness to dexamethasone and chemotherapy. Because clinical trials with this anticancer agent are expected shortly, we investigated the signaling pathway of TRAIL-induced apoptosis in MM. We detected rapid cleavage of caspases-8, -9, -3, and -6, as well as the caspase substrates poly(ADP-ribose) polymerase (PARP) and DNA fragmentation factor-45 (DFF45), but not caspase-10, upon TRAIL treatment in sensitive MM cells, pointing to caspase-8 as the apical caspase of TRAIL signaling in MM cells. These phenomena were not observed or were significantly delayed in TRAIL-resistant MM cells, suggesting that resistance may arise from inhibition at the level of caspase-8 activation. Higher levels of expression for various apoptosis inhibitors, including FLICE-inhibitory protein (FLIP), and lower procaspase-8 levels were present in TRAIL-resistant cells and sensitivity was restored by the protein synthesis inhibitor cycloheximide (CHX) and the protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM), which both lowered FLIP and cellular inhibitor of apoptosis protein-2 (cIAP-2) protein levels. Forced expression of procaspase-8 or FLIP antisense oligonucleotides also sensitized TRAIL-resistant cells to TRAIL. Moreover, the cell permeable nuclear factor (NF)-kappaB inhibitor SN50, which sensitizes TRAIL-resistant cells to TRAIL, also inhibited cIAP2 protein expression. Finally, CHX, BIM, and SN50 facilitated the cleavage and activation of procaspase-8 in TRAIL-resistant cells, confirming that inhibition of TRAIL-induced apoptosis occurs at this level and that these agents sensitize MM cells by relieving this block. Our data set a framework for the clinical use of approaches that sensitize MM cells to TRAIL by agents that inhibit FLIP and cIAP-2 expression or augment caspase-8 activity.
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PMID:Intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human multiple myeloma cells. 1238 43


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