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 killing capacity of extracts from Viscum album L., widely used as an adjuvant in complementary cancer therapy, is dependent on the content of toxic proteins, especially the mistletoe lectins (ML). Although one may expect a homogeneous distribution of 'receptors' for these proteins on the cell surface, the sensitivity of cells to the ML-mediated cytotoxicity obviously differs, as the galNAc-binding ML III in contrast to the gal-binding ML I selectively killed CD8+ lymphocytes with a 'memory' phenotype (CD62Llo), while CD19+ B cells remained almost unaffected. B cells hardly bind ML III but did bind the gal-specific ML I. In accordance with these observations, in leukaemic B cells from patients with B chronic lymphocytic leukaemia and the human IgE-secreting myeloma cell line U-266 a strong induction of apoptosis-associated mitochondrial Apo2.7 molecules was observed after treatment with ML I and less effectively by ML III, while in the leukaemic T cell line Molt-4 both ML were strong inductors of apoptosis. In the light of these findings, the possible impact of ML I- and ML III-rich mistletoe extracts in the treatment of B cell neoplasia has to be carefully investigated.
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PMID:Differential binding of toxic lectins from Viscum album L., ML I and ML III, to human lymphocytes. 1069 16

Highly malignant myeloma cells up-regulate their Fas-ligand (Fas-L) to escape immune surveillance by Fas(+) cytotoxic cells. Here it is demonstrated that this abnormality is involved in the pathogenesis of the severe anemia associated with progression of multiple myeloma (MM). By measuring Fas and Fas-L in plasma cells and erythroblasts from 19 MM patients and 5 with monoclonal gammopathies of undetermined significance (MGUS), it was found that both Fas-L(+) myeloma cells and Fas(+) erythroid progenitors were significantly increased in patients with stage III MM whose erythroblasts, cultured in the presence of autologous plasma cells or their supernatant, underwent prompt apoptosis as evaluated by propidium iodide staining, the TUNEL assay, and detection of the APO2.7-reactive mitochondrial antigen. Flow cytometry of fresh erythroblasts revealed a considerable expression of the caspases CPP32 and FLICE in both their constitutive proenzymatic forms and in cleaved subunits. By contrast, their intracytoplasmic expression was defective in patients with inactive disease and MGUS controls. The evidence that Fas-L(+) myeloma clones directly prime erythroblast apoptosis in vivo was further supported by the occurrence of fluorescein isothiocyanate-TUNEL(+) erythroblasts juxtaposed to myeloma cells in bone marrow smears. These results strongly suggest that the deregulated apoptosis in myeloma clones plays an active role in the progressive destruction of the erythroid matrix by a cytotoxic mechanism based on up-regulation of Fas-L.
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PMID:Fas-L up-regulation by highly malignant myeloma plasma cells: role in the pathogenesis of anemia and disease progression. 1122 56

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

TNF-related apoptosis-inducing ligand (TRAIL) shares significant homology with CD95 (Fas) ligand and has the ability to induce apoptosis in sensitive cells through a caspase-mediated pathway. We have evaluated the activity of purified human recombinant soluble TRAIL (S-TRAIL, comprising residues 114-281; Biomol, Plymouth Meeting, PA, USA) and a leucine zipper construct of TRAIL (LZ-TRAIL; Immunex, Seattle WA, USA) against myeloma cell lines NCI H929, U266, RPMI 8226, the FasL-sensitive Jurkat T cell ALL line, the lymphoblastoid cell line MC/CAR and primary tumour cells from 16 myeloma patients. Furthermore, we examined the relationship between TRAIL-induced apoptosis and TRAIL receptor expression utilising RT-PCR and flow cytometry. Two of three myeloma cell lines and Jurkat were TRAIL sensitive whereas MC/CAR was relatively resistant. Five of 16 (31%) primary tumours demonstrated > or =20% reduction in myeloma cells following TRAIL incubation (20-59%). This did not correlate with prior therapy. Four cell lines (two sensitive) and five primary tumours (two sensitive) demonstrated mRNA expression of the intra-cellular death domain containing TRAIL-R1. Variable expression of the two decoy (TRAIL-R3 and R4) and soluble (osteoprotegerin) receptors was seen and this did not correlate with TRAIL resistance. We conclude that myeloma cell expression of death effector receptors for TRAIL is insufficient to confer sensitivity to TRAIL-induced apoptosis but that in a significant minority of patients, irrespective of prior therapy, tumour cells are sensitive to TRAIL. The further investigation of TRAIL as an adjunct to presently available therapies for myeloma is justified.
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PMID:TRAIL-induced eradication of primary tumour cells from multiple myeloma patient bone marrows is not related to TRAIL receptor expression or prior chemotherapy. 1158 25

Monoclonal antibody 2E12 was prepared by immunization of mice with fresh cells of chronic myeloid leukemia cell line MOLM-7. A panel of 15 leukemic cell lines (myeloid, promyelocytic, erythroid, B and T lymphoid) and numerous cultured patient's leukemia and myeloma cells were tested for reactivity with 2E12 antibody. A subset of cells in all cell lines and various number of patient's cells cultivated for 10 days or more were 2E12 positive. KG-1 and HL-60 cell lines were treated by camptothecin (CAM) (5 microg/ml, 4 h), washed and further cultivated without CAM. After 24 and 48 h in culture a considerable increase of 2E12 positivity was detected both in KG-1 and HL-60 cells, which well correlated with the increase of APO2.7 positivity and the sub-G1 peaks. The 2E12 positive cells were morphologically the same as cells in PCD, possibly apoptosis. We suggest that the 2E12 antibody detects a strong antigen on apoptotic cells which could be a part of the signaling process for ingestion by phagocytes.
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PMID:Monoclonal antibody to human chronic myeloid leukemia cell line MOLM-7 specifically reacts with an antigen of apoptotic cells. 1173 3

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

Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) promote the proliferation of multiple myeloma (MM) cells and protect them against dexamethasone (Dex)-induced apoptosis. We have previously shown that Apo2 ligand/TNF-Related apoptosis inducing ligand (Apo2L/TRAIL) induces apoptosis of MM cells, including cells either sensitive or resistant to Dex and cytotoxic drugs, and overcomes the growth and survival effect of IL-6; conversely, NF-kappaB transcriptional activity attenuates their Apo2L/TRAIL-sensitivity. In the current study, we demonstrate that IGF-1 stimulates sustained activation of NF-kappaB and Akt; induces phosphorylation of the FKHRL-1 Forkhead transcription factor; upregulates a series of intracellular anti-apoptotic proteins including FLIP, survivin, cIAP-2, A1/Bfl-1, and XIAP; and decreases Apo2L/TRAIL-sensitivity of MM cells. In contrast, IL-6 does not cause sustained NF-kappaB activation, induces less pronounced Akt activation and FKHRL-1 phosphorylation than IGF-1, and increases the expression of only survivin. Forced overexpression of constitutively active Akt in MM-1S cells reduced their sensitivity to Apo2L/TRAIL and to doxorubicin (Doxo). In contrast, the Akt inhibitor IL-6-Hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate induced cell death of both Dex- and Doxo-sensitive and -resistant cells; opposed the protective effect of constitutive Akt activity against Apo2L/TRAIL; and abrogated the NF-kappaB activation, increase of anti-apoptotic proteins and protection against Apo2L/TRAIL induced by IGF-1. These findings therefore define an important role of the Akt pathway in modulating tumor cell responsiveness to Apo2L/TRAIL, delineate molecular mechanisms for the survival effects of IGF-1, and characterize differential pathophysiologic sequelae of IGF-1 vs IL-6 on MM cells. Importantly, they provide the basis for future clinical trials in MM combining conventional or novel agents with strategies designed to neutralize IGF-1.
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PMID:Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. 1217 37

Arsenic trioxide (ATO) has been shown to induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells concomitant with down-regulation of the PML-RARalpha fusion protein, a product of the t(15:17) translocation characteristic of APL leukemic cells. However, ATO is also a potent inducer of apoptosis in a number of other cancer cells lacking the t(15:17) translocation. The exact mechanism of ATO-induced apoptosis in these cells is not yet clear. We tested the effect of ATO on 7 myeloma cell lines with varying p53 status and report that in cells with mutated p53, ATO induced rapid and extensive (more than 90%) apoptosis in a time- and dose-dependent manner concomitant with arrest of cells in G(2)/M phase of the cell cycle. Myeloma cells with wild-type (wt) p53 were relatively resistant to ATO with maximal apoptosis of about 40% concomitant with partial arrest of cells in G(1) and up-regulation of p21. The use of caspase blocking peptides, fluorescence-tagged caspase-specific substrate peptides, and Western immunoblotting confirmed the involvement of primarily caspase-8 and -3 in ATO-induced apoptosis in myeloma cells with mutated p53 and primarily caspase-9 and -3 in cells expressing wt p53. We also observed up-regulation by ATO of R1 and R2 APO2/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors. Most important, however, we observed a synergy between ATO and APO2/TRAIL in the induction of apoptosis in the partially resistant myeloma cell lines and in myeloma cells freshly isolated from myeloma patients. Our results justify the use of the combination of these 2 drugs in clinical setting in myeloma patients.
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PMID:Arsenic trioxide-induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL. 1253 93


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