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)

The signal transducer and activator of transcription molecules (Stats) play key roles in cytokine-induced signal transduction. Recently, it was proposed that constitutively activated Stat 3 (Stat 3 phosphorylated) contributes to the pathogenesis of multiple myeloma (MM) by preventing apoptosis and inducing proliferation. The study aim was to investigate Stat 3 activation in a series of multiple myeloma (MM) cases and its effect on downstream targets such as the anti-apoptotic proteins Bcl-xL, Mcl-1, and Bcl-2, and the cell-cycle protein cyclin D1. Forty-eight cases of MM were analyzed. Immunohistochemistry was performed on paraffin sections using antibodies against cyclin D1, Bcl-2, Bcl-xL, Mcl-1, p21, Stat 3, and Stat 3 phosphorylated (P). Their specificity was corroborated by Western blot analysis using eight human MM cell lines as control. The proliferation rate was assessed with the antibody MiB1. In addition, the mRNA levels of cyclin D1 and Stat 3 were determined by quantitative real-time reverse transcriptase-polymerase chain reaction of paraffin-embedded microdissected tissue. Three different groups determined by the expression of Stat 3P and cyclin D1 (protein and mRNA) were identified: group 1, Stat 3-activated (23 cases, 48%). All cases revealed nuclear expression of Stat 3P. No elevation of Stat 3 mRNA was identified in any of the cases. Three cases in this group showed intermediate to low cyclin D1 protein and mRNA expression. Group 2 included 15 (31%) cases with cyclin D1 staining and lack of Stat 3P. All cases showed intermediate to high levels of cyclin D1 mRNA expression. Group 3 included 10 (21%) cases with no expression of either cyclin D1 or Stat 3P. High levels of anti-apoptotic proteins Bcl-xL and Mcl-1 were identified in 89% and 100% of all cases, respectively. In contrast to Bcl-xL and Mcl-1, the expression of Bcl-2 showed an inverse correlation with proliferation rate (P: 0.0003). No significant differences were found between the three groups in terms of proliferation rate or expression of anti-apoptotic proteins. However, cyclin D1+ cases were always well differentiated and were more likely to show a lymphoplasmocytoid differentiation (chi-square = 9.55). Overall, constitutive activation of Stat 3 was found in almost half (48%) of the investigated MM cases. However, this does not seem to have a major impact on the expression of anti-apoptotic proteins and proliferation. We showed that cyclin D1 overexpression and Stat 3 activation are, mutually exclusive events in MM (P = 0.0066). The universal expression of Mcl-1, independent of activated Stat 3, suggests that its expression is constitutive and that it might play an important role in the pathogenesis of MM.
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PMID:Analysis of signal transducer and activator of transcription 3 (Stat 3) pathway in multiple myeloma: Stat 3 activation and cyclin D1 dysregulation are mutually exclusive events. 1270 28

Indolent lymphoproliferative disorders such as Waldenstrom's macroglobulinemia (WM) are characterized by defective apoptosis, which leads to progressive accumulation of slowly dividing neoplastic lymphocytes. Activation of nuclear factor kappa B (NFkappaB) is considered to have a central pathogenic role in some hematological malignancies, including multiple myeloma, Hodgkin's disease, and extranodal marginal zone lymphoma (ENMZL). NFkappaB activation may inhibit apoptosis through the transactivation of genes such as Bcl-2 and may therefore be an important mechanism in indolent lymphoproliferative disorders, including WM. In order to assess this potential mechanism, we used immunohistochemistry to determine the presence and subcellular localisation of the major NFkappaB subunits p50 and p65. Nuclear staining of NFkappaB subunits (indicative of activation) was not seen in any of the 40 cases examined. Thirty-seven (95%) cases showed cytoplasmic positivity for both p50 and p65 and one case demonstrated cytoplasmic staining for p65 alone, while the two remaining cases showed complete absence of staining. We would therefore conclude that NFkappaB activation is not a feature of WM and that alternative mechanisms of apoptosis inhibition should be investigated in this disorder.
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PMID:Dysregulation of apoptosis in Waldenstrom's macroglobulinemia does not involve nuclear factor kappa B activation. 1272 Jan 28

Bcl-2 is an attractive target for anticancer therapy in a number of malignancies, as its expression is associated with inhibition of the apoptotic program and resistance to traditional therapeutic agents. Bcl-2 antisense therapy with G3139 (oblimersen sodium; Genasense, Genta Inc, Berkeley Heights, NJ) is in clinical trials for a number of malignancies, including an ongoing trial in myeloma. In vitro G3139 has been shown to downregulate Bcl-2 in myeloma cells, sensitizing them to chemotherapeutic agents. We have undertaken a project to evaluate antisense inhibition strategies in Waldenstrom's macroglobulinemia (WM), and whether the Bcl-2 pathway may provide a therapeutic target in this disease. We have shown that Bcl-2 is expressed in WM cells in vitro and that downregulation of Bcl-2 may be achieved by treatment with G3139. Treatment of WM cells with G3139 is associated with increased cell death and shows potential synergy with chemotherapeutic agents active in WM. Bcl-2 downregulation via G3139 antisense treatment may have potential anticancer efficacy in WM and further studies to address its effects on clinical specimens are warranted, in anticipation of using this agent in WM clinical trials.
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PMID:Modulation of the activity of Bcl-2 in Waldenstrom's macroglobulinemia using antisense oligonucleotides. 1272 Jan 56

The components of the apoptotic pathway are targets for anticancer therapy. Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies. Oblimersen sodium (G3139, Genasense, Genta Inc, Berkeley Heights, NJ) is an antisense oligonucleotide compound designed to specifically bind to the first six codons of the human bcl-2 mRNA sequence, resulting in degradation of bcl-2 mRNA and subsequent decrease in Bcl-2 protein translation. Oblimersen is the first oligonucleotide to demonstrate proof of principle of an antisense effect in human tumors by the documented downregulation of the target Bcl-2 protein. A growing body of preclinical and clinical evidence suggests that oblimersen synergizes with many cytotoxic and biologic/immunotherapeutic agents against a variety of hematologic malignancies and solid tumors. Randomized clinical trials are currently underway to evaluate the efficacy and tolerability of oblimersen in combination with cytotoxic chemotherapy in chronic lymphocytic leukemia (CLL), multiple myeloma (MM), malignant melanoma, and non-small cell lung cancer. In addition, nonrandomized trials are underway to evaluate oblimersen in non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), and hormone-refractory prostate cancer. Preclinical data support the clinical evaluation of oblimersen in additional tumor types, including chronic myelogenous leukemia, and breast, small cell lung, gastric, colon, bladder (CML), and Merkel cell cancers. Enhancement of the efficacy of anticancer treatments with oblimersen Bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy, and ongoing clinical trials will test this therapeutic approach.
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PMID:Oblimersen sodium (G3139 Bcl-2 antisense oligonucleotide) therapy in Waldenstrom's macroglobulinemia: a targeted approach to enhance apoptosis. 1272 Jan 57

Interleukin-6 (IL-6) is a major survival factor for malignant plasma cells involved in multiple myeloma. Using an RNase protection assay, we looked for gene expression of 10 anti- and proapoptotic Bcl-2-family proteins in 12 IL-6-dependent human myeloma cell lines (HMCL). A high Mcl-1 gene expression was found in all HMCLs and the other genes were variably expressed. Out of the 10 Bcl-2-family members, only the Mcl-1 gene was regulated by IL-6. Upon starvation of IL-6, Mcl-1 gene expression decreased in association with myeloma cell apoptosis and was upregulated after adding IL-6 again in association with myeloma cell survival. A constitutive Mcl-1 expression was induced with an Mcl-1-GFP retrovirus in two IL-6-dependent HMCLs. The Mcl-1 HMCLs have a marked reduced apoptosis upon IL-6 starvation compared to HMCLs transduced with control GFP retrovirus and may grow without adding IL-6. These data emphasize the major role of Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells.
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PMID:A major role for Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells. 1277 46

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

Bortezomib, a proteasome inhibitor, shows substantial anti-tumor activity in a variety of tumor cell lines, is in phase I, II, and III clinical trials and has recently been approved for the treatment of patients with multiple myeloma. The sequence of events leading to apoptosis following proteasome inhibition by bortezomib is unclear. Bortezomib effects on components of the mitochondrial apoptotic pathway were examined: generation of reactive oxygen species (ROS), alteration in the mitochondrial membrane potential (Delta psi m), and release of cytochrome c from mitochondria. With human H460 lung cancer cells, bortezomib exposure at 0.1 microM showed induction of apoptotic cell death starting at 24 h, with increasing effects after 48-72 h of treatment. After 3-6 h, an elevation in ROS generation, an increase in Delta psi m, and the release of cytochrome c into the cytosol, were observed in a time-dependent manner. Co-incubation with rotenone and antimycin A, inhibitors of mitochondrial electron transport chain complexes I and III, or with cyclosporine A, an inhibitor of mitochondrial permeability transition pore, resulted in inhibition of bortezomib-induced ROS generation, increase in Delta psi m, and cytochrome c release. Tiron, an antioxidant agent, blocked the bortezomib-induced ROS production, Delta psi m increase, and cytochrome c release. Tiron treatment also protected against the bortezomib-induced PARP protein cleavage and cell death. Benzyloxycarbonyl-VAD-fluoromethyl ketone, an inhibitor of pan-caspase, did not alter the bortezomib-induced ROS generation and increase in Delta psi m, although it prevented bortezomib-induced poly(ADP-ribose) polymerase cleavage and apoptotic death. In PC-3 prostate carcinoma cells (with overexpression of Bcl-2), a reduction of bortezomib-induced ROS generation, Delta psi m increase was correlated with cellular resistance to bortezomib and the attenuation of drug-induced apoptosis. The transient transfection of wild type p53 in p53 null H358 cells caused stimulation of the bortezomib-induced apoptosis but failed to enhance ROS generation and Delta psi m increase. Thus ROS generation plays a critical role in the initiation of the bortezomib-induced apoptotic cascade by mediation of the disruption of Delta psi m and the release of cytochrome c from mitochondria.
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PMID:Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells. 1282 77

An increasing number of model systems of plasma cell tumor (PCT) formation have been and are being developed. Discussed here are six models in mice and multiple myeloma (MM) in humans. Each model illustrates a unique set of biological factors. There are two general types of model systems: those that depend upon naturally arising mutagenic changes (pristane-induced PCTs, 5TMM, and MM) and those that are associated with oncogenes (Emu-v-abl), growth factors [interleukin-6 (IL-6)], and anti-apoptotic factors (Bcl-xL/Bcl-2). PCTs develop in several special tissue microenvironments that provide essential cytokines (IL-6) and cell-cell interactions. In mice, the activation and deregulation of c-myc by chromosomal translocations is a major feature in many of the models. This mechanism is much less a factor in MM and the 5T model in mice. Genetically determined susceptibility is involved in many of the mouse models, but only a few genes have been implicated thus far.
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PMID:Neoplastic development in plasma cells. 1284 15

PS-341, a potent and selective proteasome inhibitor, is the prototype for a new class of therapeutics that targets the ubiquitin-proteasome pathway. It is active as a single agent and potentiates chemotherapy and radiation in pre-clinical models. Early phase clinical studies have demonstrated tolerability and activity in multiple myeloma, lymphoma, prostate cancer and lung cancer. By its mechanism of inhibiting protein degradation, PS-341 targets a wide-range of pathways that are relevant to tumor progression and therapy resistance, and can directly modulate expression of cyclins, p27(Kip1), p53, NF-kappaB, Bcl-2 and Bax. PS-341 is currently in phase I/II clinical development in lung cancer. This paper will review the pre-clinical and clinical experience with PS-341 as it relates to lung cancer.
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PMID:Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer. 1286 67

Apo2 Ligand or Tumour Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (Apo2L/TRAIL) is a member of the TNF gene superfamily that selectively induces apoptosis in tumor cells of diverse origins through engagement of death receptors. We have recently demonstrated that Type I interferons (IFN-alpha and beta) induce apoptosis in multiple myeloma (MM) cell lines and in plasma cells from MM patients. Moreover, Apo2L selectively induces apoptosis of patient MM tumor cells while sparing non-malignant cells. Apo2L induction is one of the earliest events following IFN administration in these cells. IFNs activate Caspases and the mitochondrial-dependent apoptotic pathway mediated by Apo2L production. Cell death induced by IFNs and Apo2L can be blocked by a dominant-negative Apo2L receptor, DRS, and is regulated by members of the Bcl-2 family of proteins. This review is focused on the apoptotic signaling pathways regulated by Apo2L and Bcl-2-family proteins and summarizes what is known about their clinical role.
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PMID:Role of Apo2L/TRAIL and Bcl-2-family proteins in apoptosis of multiple myeloma. 1291 74


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