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)

Arsenic trioxide (ATO) is emerging as a standard therapy for refractory acute promyelocytic leukemia. Consequently, ATO-based therapies are being investigated in other cancers. We have reported that the combination of ATO and ascorbic acid is an effective strategy in chemoresistant myeloma cell lines and in plasma cells from patients. ATO action is multimodal and appears to involve thiol depletion, increased reactive oxygen species production, loss of mitochondrial membrane potential (DeltaPsi(m)), and activation of caspases. To better define the ATO death pathway, we asked whether caspase activity is required for ATO-mediated cell death. Here we report that ATO exerts cytotoxic effects in myeloma cell lines via both caspase-dependent and caspase-independent pathways. We monitored ATO-induced changes in cell viability, caspase activity, superoxide production, and DeltaPsi(m) in the presence or absence of the caspase inhibitors t-butoxy carbonyl-Asp.fluoromethylketone (BocD.fmk) and Z-Val-Ala-Asp.fluoromethylketone (zVAD.fmk) and the anti-oxidant N-acetylcysteine. Consistent with glutathione levels dictating ATO action, N-acetylcysteine abrogated ATO-induced changes in cell death, caspase activation, free radical production, and loss of DeltaPsi(m) in all the cell lines we tested. Experiments with caspase inhibitors suggested at least two models for ATO death signaling. In 8226/S cells, blockade of caspases had no effect on loss of cell viability, increase in reactive oxygen species production, and minimal effects on the loss of DeltaPsi(m). In contrast, BocD.fmk or zVAD.fmk conferred significant protection from the effects of ATO in U266 cells and MM1.S cells. Chemoresistant variants of 8226/S and MM1.S displayed similar ATO-induced death pathways as their respective parental lines. Studies with myeloma cells from bone marrow biopsies indicated that ATO initiates a caspase-independent pathway in the majority of samples.
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PMID:Arsenic trioxide uses caspase-dependent and caspase-independent death pathways in myeloma cells. 1461 89

All-trans retinoic acid (ATRA) is a natural oxidative metabolite of Vitamin A (retinol) and is known to be a regulator of cell proliferation differentiation, especially in various malignant cells. The cyto-differentiating action of ATRA has led to its usage in the treatment of several malignancies, particularly acute promyelocytic leukemia (APL). There have been many reports regarding the cell biological effects of ATRA on human myeloma cells and a few clinical trials. Most of these reports have revealed growth inhibition by ATRA mediated by down-regulation of the IL-6/IL-6R auto/paracrine loop, and upregulation of p21/Cip1. Here, we review previous reports and introduce experimental results obtained using various myeloma cell lines established in our laboratory.
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PMID:Effects of all-trans retinoic acid (ATRA) on human myeloma cells. 1469 15

Arsenic trioxide (As2O3) is an effective therapy for acute promyelocytic leukemia (APL), and there has been promising activity noted in other hematologic and solid tumors. The mechanism of action of As2O3 such as differentiation and apoptosis has prompted study into combination therapy. Furthermore, the connection of the sensitivity of diseases such as APL and multiple myeloma to oxidative damage has allowed the investigation of pharmacologic modulation of the cellular redox state for potentiation of As2O3. Continued study of As2O3 as a single-agent and in combination therapy will allow identification of the safest and most effective treatment regimens for malignant disease.
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PMID:The potential of arsenic trioxide in the treatment of malignant disease: past, present, and future. 1523 63

These studies explore the molecular effect of arsenicals on MM cells. Freshly isolated cells derived from patients with advanced, chemo-refractory myeloma as well as human myeloma cell lines, ARP-1, RPMI-8226 and H929 were exposed to the organic arsenical melarsoprol and to the inorganic compound AT. Both agents potently induced apoptosis in myeloma cells. Exposure to 1-5 microM AT or melarsoprol for 6 hours suppressed NF-kappa B DNA binding and enhanced of c-Jun kinase (JNK) activity. Arsenic also activated caspase-3 resulting in the cleavage of poly (ADP-ribose) polymerase (PARP) and Fas/TNF alpha related receptor interacting protein (RIP). In contrast to reported observations in acute promyelocytic leukemia, myeloma cell apoptosis was not associated with either the downregulation of Bcl-2 protein or with alterations in the expression of other Bcl-2 family members, Bax, Bak, Bag, and Bcl-xl. This study first shows that arsenic induces apoptotic signaling in MM through the cleavage of TNF alpha related receptor interacting protein (RIP). RIP is a key downstream protein in FasL/ TNF alpha /TRAIL induced apoptosis and a major antiapoptotic adaptor of pathways through NF-kappa B and JNK. RIP has not been previously characterized in myeloma. This study supports the hypothesis that arsenicals share common mediators (RIP, NF-kappa B, PARP, caspase-3) with death receptor induced apoptosis. These studies provide an important insight into the molecular mechanism of AT induced apoptosis and can be used in the development of adjuvant therapy for MM, presently an incurable disease.
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PMID:RIP kinase is involved in arsenic-induced apoptosis in multiple myeloma cells. 1531 84

Interferon (IFN) induces expression of proapoptotic genes and has been used in the clinical treatment of multiple myeloma. The promyelocytic leukemia (PML) gene is an IFN-induced target that encodes a tumor suppressor protein. PML protein is typically localized within discrete speckled nuclear structures termed PML nuclear bodies (NBs). Multiple myeloma cells demonstrate differential responses to IFN treatment, the mechanism of which is largely unknown. Herein, we show that growth inhibition effects of IFN-alpha in myeloma cells correlate with PML NBs and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induction, whereas known IFN targets including signal transducer and activator of transcription-1 (STAT1), STAT3, p38, and Daxx cannot account for these differential responses. RNAi silencing of PML blocks IFN-alpha-induced apoptosis in myeloma cells and correspondingly down-regulates TRAIL expression. Similarly, stable expression of a dominant negative TRAIL receptor DR5 partially blocks IFN-induced cell death. These results demonstrate that PML and TRAIL play important roles in IFN-induced apoptosis and identify TRAIL as a novel downstream transcriptional target of PML. Identification of PML and PML NBs as effectors of IFN responses provides insights into mechanisms by which tumor cells exhibit resistance to this class of agents and may prove useful in assessing treatment regimens.
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PMID:PML mediates IFN-alpha-induced apoptosis in myeloma by regulating TRAIL induction. 1545 16

Although arsenic trioxide (As(2)O(3)) is an effective therapy in acute promyelocytic leukemia (APL), its use in other malignancies is limited by the toxicity of concentrations required to induce apoptosis in non-APL tumor cells. We looked for agents that would synergize with As(2)O(3) to induce apoptosis in malignant cells, but not in normal cells. We found that trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a widely known antioxidant, enhances As(2)O(3)-mediated apoptosis in APL, myeloma, and breast cancer cells. Treatment with As(2)O(3) and trolox increased intracellular oxidative stress, as evidenced by heme oxygenase-1 (HO-1) protein levels, c-Jun terminal kinase (JNK) activation, and protein and lipid oxidation. The synergistic effects of trolox may be specific to As(2)O(3), as trolox does not add to toxicity induced by other chemotherapeutic drugs. We explored the mechanism of this synergy using electron paramagnetic resonance and observed the formation of trolox radicals when trolox was combined with As(2)O(3), but not with doxorubicin. Importantly, trolox protected nonmalignant cells from As(2)O(3)-mediated cytotoxicity. Our data provide the first evidence that trolox may extend the therapeutic spectrum of As(2)O(3). Furthermore, the combination of As(2)O(3) and trolox shows potential specificity for tumor cells, suggesting it may not increase the toxicity associated with As(2)O(3) monotherapy in vivo.
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PMID:Trolox selectively enhances arsenic-mediated oxidative stress and apoptosis in APL and other malignant cell lines. 1546 33

This session addressed acute promyelocytic leukemia (APL), multiple myeloma, and myelodysplastic syndromes. In particular, arsenic trioxide as a treatment for APL, one of the most highly curable types of acute myeloid leukemia, was discussed. Speakers also discussed the use of combination regimens in clinical trials for multiple myeloma treatments and therapeutic agents in the treatment of myelodysplastic syndromes.
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PMID:Nursing considerations for nontraditional treatment approaches to hematologic malignancies. 1547 94

In multiple myeloma (MM), the interaction between myeloma cells and bone marrow microenvironment has an important role in the pathogenesis of MM. We first examined the inducing effect of myeloma cells on migration of human umbilical vein vascular endothelial cells (HUVECs). Five myeloma cell lines produced varying amounts of VEGF, and migration of HUVECs was induced by coculture with myeloma cells. We next examined the inhibitory effect of a novel synthetic retinoid Am80 (Tamibarotene) on both myeloma cells and HUVECs. Am80 is specific for the retinoic-acid receptor-alpha/beta, and has therapeutic effects in all-trans retinoic acid resistant acute promyelocytic leukemia. Am80 slightly inhibited the growth of both myeloma cells and HUVECs, and remarkably inhibited the growth of HUVECs stimulated by VEGF. Am80 showed little growth inhibition of bone marrow stromal cells (BMSCs), but it markedly inhibited migration of HUVECs by cocultured myeloma cells. Am80 inhibited VEGF-induced phosphorylation of VEGF receptor. In addition, VEGF-induced formation of tube-like structures in vitro and neovascularization in mouse corneas were significantly inhibited by Am80. These findings clearly demonstrate that Am80 is a potential inhibitor of angiogenesis caused by the interaction between vascular endothelial cells and myeloma cells, and might be a useful therapeutic agent against MM.
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PMID:Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis. 1584 26

Arsenic, first among the top environmentally hazardous substances, is associated with skin, lung, liver, kidney, prostate, and bladder cancer. Arsenic is also a cardiovascular and a central nervous system toxicant, and it has genotoxic and immunotoxic effects. Paradoxically, arsenic trioxide is used successfully in the treatment of acute promyelocytic leukemia and multiple myeloma. Arsenic induces oxidative stress, and its toxicity is decreased by free thiols and increased by glutathione depletion. To further characterize the role of glutathione and oxidative stress in the toxicity of arsenic, we have used fetal fibroblasts from Gclm(-/-) mice, which lack the modifier subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis. Gclm(-/-) mouse embryo fibroblasts (MEFs) are eight times more sensitive to arsenite-induced apoptotic death. Because of a dramatic decrease in glutathione levels, Gclm(-/-) MEFs have a high prooxidant status that is not significantly relieved by treatment with the phenolic antioxidant tBHQ; however, tBHQ blocks arsenite-induced apoptosis in both Gclm(+/+) and Gclm(-/-) cells, although it raises a significant antioxidant response only in Gclm(+/+) cells. Global gene expression profiles indicate that tBHQ is significantly effective in reversing arsenite-induced gene deregulation in Gclm(+/+) but not in Gclm(-/-) MEFs. This effect of tBHQ is evident in the expression of metalloproteases and chaperones, and in the expression of genes involved in DNA damage and repair, protein biosynthesis, cell growth and maintenance, apoptosis, and cell cycle regulation. These results suggest that regulation of glutathione levels by GCLM determines the sensitivity to arsenic-induced apoptosis by setting the overall ability of the cells to mount an effective antioxidant response.
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PMID:Butylhydroquinone protects cells genetically deficient in glutathione biosynthesis from arsenite-induced apoptosis without significantly changing their prooxidant status. 1601 39

The proven efficacy of ATO in the treatment of APL and the emerging importance of ATO in other diseases prompted extensive studies of the mechanisms of action of ATO in APL and in other types of cancers. In this review we will focus on downstream events in ATO-induced intrinsic and extrinsic apoptotic pathways with an emphasis on the role of pro-apoptotic and anti-apoptotic proteins and the role of p53 in ATO-induced apoptosis including its effect on cell cycle, its anti-mitotic effect and the role of apoptosis inducing factors (AIF) in ATO-induced apoptosis, chromatin condensation and nuclear fragmentation in myeloma cells as a model.
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PMID:Arsenic trioxide: an anti cancer missile with multiple warheads. 1601 69


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